key: cord-0725953-6b7ub83x
authors: Hirano, Toshio
title: Interleukin 6 in inflammation, autoimmunity and cancer
date: 2020-12-18
journal: Int Immunol
DOI: 10.1093/intimm/dxaa078
sha: 5267745222f46412b2c4408c5a9306363e5b81e6
doc_id: 725953
cord_uid: 6b7ub83x

Interleukin 6 (IL-6) is involved both in immune responses and in inflammation, hematopoiesis, bone metabolism and embryonic development. IL-6 plays roles in chronic inflammation (closely related to chronic inflammatory diseases, autoimmune diseases and cancer) and even in the cytokine storm of corona virus disease 2019 (COVID-19). Acute inflammation during the immune response and wound healing is a well-controlled response, whereas chronic inflammation and the cytokine storm are uncontrolled inflammatory responses. Non-immune cells and immune cells, cytokines such as IL-1β, IL-6 and tumor necrosis factor alpha (TNFα) and transcription factors nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) play central roles in inflammation. Synergistic interactions between NF-κB and STAT3 induce the hyper-activation of NF-κB followed by the production of various inflammatory cytokines. Because IL-6 is a NF-κB target, simultaneous activation of NF-κB and STAT3 in non-immune cells triggers a positive feedback loop of NF-κB activation by the IL-6–STAT3 axis. This positive feedback loop is called the IL-6 amplifier (IL-6 Amp) and is a key player in the local initiation model, which states that local initiators, such as senescence, obesity, stressors, infection, injury and smoking, trigger diseases by promoting interactions between non-immune cells and immune cells. This model counters dogma that holds that autoimmunity and oncogenesis are triggered by the breakdown of tissue-specific immune tolerance and oncogenic mutations, respectively. The IL-6 Amp is activated by a variety of local initiators, demonstrating that the IL-6–STAT3 axis is a critical target for treating diseases.

Cytokines function in many fundamental processes for life and disease including immunity, inflammation, embryonic development, regeneration, angiogenesis, metabolism, obesity, aging and so on. Among these diverse functions, their roles in inflammation have attracted attention in relation to disease development and treatment.

Inflammation is involved in homeostasis and regenerative processes such as wound healing. It is also involved in acute phase reactions and immune responses against pathogens. In these cases, inflammation is well controlled. On the other hand, chronic inflammation and cytokine storm are uncontrolled forms of inflammation. The former plays crucial roles in the development of many complex diseases and disorders such as chronic inflammatory diseases, including metabolic syndrome, neurodegenerative diseases and cardiovascular diseases, along with autoimmune diseases and cancer (1-11). Cytokine storm has received a great deal of attention in connection with the pathology of corona virus disease 2019 (COVID-19) (12-17). Cytokine storm is considered a type of inflammation where the massive production of inflammatory cytokines is acutely induced in a dysregulated manner in response to infection, trauma, chimeric antigen-receptor T cell (CAR-T) therapy and so on. In this regard, inflammation is a double-edged sword in that it is dependent on the context, location and timing, making it difficult to develop therapeutics.

Inflammation is a complex process in which a variety of cells, including B lymphocytes, T lymphocytes, myeloid cells, epithelial cells, fibroblasts, endothelial cells, muscle cells and adipocytes interact with each other through membrane associated molecules, metalloproteases (MMPs) and soluble factors, such as cytokines, chemokines and growth factors. Pro-inflammatory cytokines such as interleukin-1 beta (IL-1, tumor necrosis factor alpha (TNF) and IL-6 play crucial roles in inflammation. Among them, IL-6 is a major player in chronic inflammatory diseases, autoimmune diseases, cancer and cytokine storm (1,3,10-26). IL-6, which was discovered in 1986 (27), is a pleiotropic cytokine involved not only in immune responses but also in inflammation, hematopoiesis, bone metabolism, embryonic development and other fundamental processes (1,21,28-32). IL-6 is a prototypical member of the IL-6 family of cytokines, which is composed of 10 members including IL-6, IL-11, IL-27, oncostatin M (OSM), leukemia inhibitory-factor (LIF), ciliary neurotrophic factor (CNTF), cardiotrophin 1 (CT-1), cardiotrophin-like cytokine factor 1 (CLCF1), IL-35 and IL-39 (33). It was originally identified as B cell Stimulating Factor-2 (BSF-2), an inducer of immunoglobulin production (27) . Several other proteins including interferon beta 2 (IFN2) (34), IL-1-induced 26-kDa protein (35), plasmacytoma/hybridoma/myeloma growth factor (36-38) and hepatocyte-stimulating factor (39,40) were found to be identical to BSF-2 and thus IL-6 (41). These studies indicated that IL-6 has a variety of functions not only in health but also in diseases, such as plasmacytoma and myeloma.

Studies in the 1980s also showed that IL-6 is produced by cardiac myxoma cells (42) and Castleman's germinal center cells (43) and is present at high amounts in the IL-6 receptor (IL-6R) is composed of an IL-6 binding receptor molecule (IL-6R) and signal transducer, gp130, which is shared among the IL-6 family of cytokines (33) (Fig. 1A) . For IL-6 activity, the expression of both IL-6R and gp130 on the cell surface is required, which limits the number of target cells on which IL-6 acts to lymphocytes, myeloid cells and hepatocytes (33). However, IL-6 complexed with the soluble form of IL-6R (sIL-6Rα) can act on cells expressing only gp130, such as heart muscle cells. Double transgenic mice expressing both IL-6 and IL-6R, but not transgenic mice expressing either IL-6 or IL-6R alone, show myocardial hypertrophy (92). In the early 1990s, it was found that IL-12 is composed of a disulfide heterodimer that included p40 and p35 subunits, resembling IL-6 and sIL-6R, respectively (93). Additionally, IL-12 acts through IL-12R, which is closely related to gp130 (94). The complex of CNTF and its soluble form of receptor alpha acts on cells expressing LIFR and gp130 (95). These early studies show that there is a mechanism by which a cytokine acquires different target specificity through complex formation with the ligand and the soluble form of the cytokine receptor subunit. Through this mechanism, a cytokine acquires novel function, namely cytokine-soluble receptor complex function, to act as a novel cytokine on target cells (1). This mode of IL-6 action is now called the trans-signaling mode, while the original membrane type is called the classic mode(96) (Fig. 1B) . The trans-signaling mode expands the range of cells that respond to IL-6, because gp130 is expressed in a wide range of cells, including endothelial cells and fibroblasts, explaining one of the mechanisms by which IL-6 acts on a wide range of cells and tissues to exert a pleiotropic function. Indeed, this mode plays crucial roles in chronic inflammation (33,96). One example has IL-6 together with sIL-6Racting on endothelial cells that express only gp130 to induce STAT3 activation, chemokine expression and the augmentation of ICAM-1, thus contributing to local inflammation by activating leukocyte recruitment (97). In addition, IL-6 and sIL-6R induce a transition between the early predominantly neutrophilic stage of an infection and the more sustained mononuclear cell influx, contributing the switch from acute to chronic inflammation (98). Further, they act on fibroblasts and endothelial cells to recruit T helper-17 (Th17) cells, leading to an RA-like joint disease (F759 M a n u s c r i p t 6 arthritis) and experimental autoimmune encephalomyelitis (EAE) (54,66,99). sIL-6Rα is generated mainly by proteolysis by ADAM17 and to a minor extent by alternative splicing in humans. Notably, sIL-6R is increased in several diseases, indicating that trans-signaling plays important roles in the progression of inflammation in many diseases including severe 96) . In certain cases, IL-6 bound to cell surface IL-6R can act on another cell that expresses gp130 in a manner consistent with the IL-6-sIL-6R complex. For example, IL-6 bound to IL-6Rα expressed on dendritic cells (DCs) directly acts on CD4(+) T cells through gp130 to induce Th17 cells (100). The signal transduction by this trans-presentation (Fig. 1B) might differ from trans-signaling, since the soluble form of gp130 efficiently inhibits trans-signaling, but not transpresentation or classical signaling (101). IL-6 activates Janus kinase (JAK) family tyrosine kinases through gp130, leading to the activation of STAT family transcription factors, mainly STAT3, as well as src homology region 2 domain-containing phosphatase 2 (SHP-2), GRB2-associated-binding protein (GAB), extracellular signal-regulated kinase (EARK) and mitogen-activated protein kinase (MAPK) signaling pathways (Fig. 1A) . Activated JAK phosphorylates tyrosine residues in the cytoplasmic domain of gp130 (30,31,61,62,102,103).

Utilizing chimeric receptors carrying the intracellular region of human gp130, it was shown that Y767, Y814, Y905 and Y915, which all have YXXQ moities, are required for STAT3 activation in vitro, and that Y759 is an SHP2 binding site (104, 105) . The binding of SHP2 to Y759 mediates activation of the ERK-MAPK cascade via the adaptor molecules GAB1 and GAB2 (106, 107) . Gp130 signaling is also mediated by the Src family kinase, Yes, which directly associates with gp130 via amino acid residues 812-827 (108). IL-6 activates the Yes-associated protein (YAP)-Notch pathway through Yes, stimulates epithelial cell proliferation and confers regeneration capacity in injured intestinal epithelia. The IL-6-Notch-3 pathway is also involved in cell growth and the promotion of a hypoxia-resistant/invasive phenotype in breast cancer development (109) .

These pathways affect each other and are negatively regulated by several molecules. The gp130-mediated activation of STAT3 is involved in the cell-cycle transition through the upregulation of cyclins D2, D3 and A, and cdc25A, and the concomitant downregulation of p21 and p27, while p21 is induced when STAT3 activation is suppressed, indicating the balance of contradictory signals determines the final output (110) . Similarly, defective STAT3 activation enhances SHP-2-ERK-MAPK activation pathways, most likely through an impaired STAT3-mediated induction of suppressor of cytokine signaling 3 (SOCS3) (111, 112) . Phosphorylated Y759 (human gp130) or Y757 (murine gp130) serves as a binding site for SOCS3 and SHP-2. In fact, knock-in mice expressing human gp130 with Y759F mutation (F759 mice) (113) or mice expressing murine gp130 with Y757F mutation (64) display splenomegary, lymphadenopathy, an enhanced acute-phase reaction and prolonged STAT3 activation. The enhanced STAT3 activation was initially considered the result of an inability to recruit SHP-2, a negative regulator having tyrosine phosphatase activity (113) (114) (115) . However, this site is also a recruitment motif for SOCS3, and it was found that the F759/F757-dependent negative A c c e p t e d M a n u s c r i p t regulation is mainly dependent on the recuirtment of SOCS3 (116, 117) . SOCS3 is induced by STAT3 and considered to regulate a major negative feedback loop of a gp130mediated signaling pathway (118) (119) (120) . In addition, TNF receptor-associated factor 5 (TRAF5) negatively regulates IL-6-gp130-mediated STAT3 activation in naïve CD4(+) T cells to suppress the Th17 differentiation (121) , while TRAF3 facilitates the association of protein tyrosine phosphatase nonreceptor type 22 (PTPN22), inhibiting STAT3 activation in B cells (122) . MiR-135a and miR-337-3p downregulate JAK2 and STAT3, respectively (123, 124) . Protein inhibitors of activated STAT (PIAS) is also shown to be a direct inhibitor of STAT3 (125) .

These multiple signal-transduction pathways intimately regulate cell survival, proliferation, inflammation, immunity, angiogenesis, and tumor development and progression through the expression of several genes (1,19,21,26,31).

Concerning cell survival and proliferation, two signals through gp130 are involved. One is the SHP-2-ERK-MAPK pathway and the other is STAT3-bcl-2-mediated cell survival (104) . STAT3 is involved not only in bcl-2 induction, but also in the induction of c-myc, cyclins and Pim1/2 kinase to regulate cell survival and cell cycle progression in a pre-B cell line (110, 126, 127) . STAT3 activation by IL-6 is required for intestinal epithelial cell survival and cell-cycle progression during colitis-induced tumorigenesis (20).

The proto-oncogene serine/threonine-protein (Pim) kinases, Pim-1 and Pim-2, are targets of STAT3 and involved in cell proliferation and cell survival together with c-myc (127) . The IL-6-STAT3-Pim kinase axis is involved in the development and cell growth of pancreatic cancer (128, 129) . In fact, Pim-1 expression in pancreatic cancer tissues and plasma Pim-1 levels are increased, and a high expression level is negatively associated with prognosis. Furthermore, high plasma Pim-1 expression is an independent adverse prognostic factor for pancreatic cancer (129) and also for breast cancer (130) . The IL-6-STAT3 pathway is involved in the epithelial-mesenchymal transition (EMT) (131, 132) , tumor migration (133) , cancer stemness (130, 134, 135) and the induction of hypoxiainducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF), two key players for angiogenesis (136) (137) (138) (139) (140) . Furthermore, oncogenic miR-21 and miR-181b are targets of IL-6-STAT3, leading to the activation of NF-B (90,141). An increased expression of miR-200 family members is associated with both tumor initiation in STAT3-dependent murine gastric cancer and early-stage gastric cancer in patient cohorts (142) . M a n u s c r i p t 8 IL-6-STAT3 signaling in immunity IL-6 was originally cloned as a factor acting on B cells to induce immunoglobulin production (27) and have a role in B cell abnormality (42). Indeed, IL-6 promotes antibody production by directly acting on plasma cells and by indirectly promoting Bcl6dependent follicular CD4(+) T (Tfh) cell differentiation together with IL-21 (143-146) (Fig. 2) . IL-6 transgenic mice show severe plasmacytosis with hypergammaglobulinemia (147) , while IL-6-deficient mice are defective in immunoglobulin production (148, 149) . Moreover, mice reconstituted with hematopoietic stem cells carrying mutant gp130 lacking STAT3 binding sites show lower serum immunoglobulin levels (113) , and Stat3 conditionally knockouted in mouse B cells results in a loss of T cell-dependent plasma cells (150) . STAT3 is also required for human plasma cell differentiation by upregulating BLIMP1 and downregulating BCL6 (151) . STAT3 loss-of-function (LOF) patients have impaired antigen-specific antibody responses (152, 153) . IL-6-induced STAT3 activation is critical for in vivo plasma cell survival and immunoglobulin secretion in humans (154) . Consistently, TRAF3 inhibits IL-6-STAT3 signaling in B cells and reduces plasma cell development (122) . In addition to the aforementioned role of IL-6 on Tfh cells, IL-6 is shown to direct the differentiation of IL-4-producing T helper type 2 (Th2) cells, while it inhibits the differentiation of interferon gamma (IFN)producing Th1 cells (155) . T cell responses against tumors are mediated by CD8(+) effector T cells (Teff), of which differentiation is dependent on IFN-secreting Th1 cells. It was shown that myeloid-derived sIL-6R complexed with IL-6 inhibits Th1 responses through STAT3-induced c-Maf. This is considered to be one of mechanisms by which IL-6 inhibits T cell immunity against tumors (156) . However, the effect of IL-6 on the diversity of Th1 and Th2 cells is not simple: IL-6 induced by repeated inflammation is responsible for Th1 cell responses in peritoneal fibrosis (157) .

IL-17-producing Th17 cells have been shown to have a crucial role in autoimmunity and a still-controversial role in cancer (pro-tumorigenic or anti-tumorigenic), whereas regulatory T (Treg) cells inhibit autoimmunity and tumor immunity (158) (159) (160) (161) (162) (163) . IL-6 together with TGF induces Th17 cells (164) (Fig. 2) . RAR-related orphan receptor gamma t (RORt) is the key transcription factor for IL-6 and TGF-induced Th17 cell differentiation (165) . On the other hand, IL-6 inhibits the TGF-induced generation of Treg cells (166) . This inhibition by IL-6 is a direct action on naïve T cells (167) . However, IL-6-mediated inhibition is restricted to inducible Treg cells and has no effect on natural Treg cells (168) .

The requirement for human naïve T cells in Th17 cell differentiation differs from that of mouse, since human T cells in the presence of IL-1 with IL-6 or IL-23 can differentiate to Th17 cells without TGF (169, 170) . However, even in the absence of TGF, the combination of IL-1, IL-6 and IL-23 induces pathogenic Th17 cells from mouse naïve T cells in vitro and in vivo, suggesting an alternate mode of Th17 cell differentiation (171) . Th17 cells generated without TGF express both RORt and T-bet, while Th17 cells generated in the presence of TGF express only RORt. IL-6 upregulates IL-23R expression in a manner dependent on STAT3, and IL-23 further enhances its own receptor expression to increase the pathogenic potential of Th17 cells (171) . Consistently, IL-23R is essential for the terminal differentiation of Th17 cells that are M a n u s c r i p t 9 capable of inducing EAE in vivo (172) . IL-6-activated STAT3 promotes Th17 cell pathogenicity by upregulating IL-1R through miR-183c induction (173) .

The IL-6-STAT3 pathway in CD4(+) T cells is essential for Th17 cell development and for the expression of RORt (174, 175) , while IL-27, a member of the IL-6 family of cytokines and activator of STAT3, inhibits Th17 cell differentiation in a manner dependent on STAT1 (176, 177) (Fig. 2) . This effect suggests that STAT1 inhibits STAT3induced Th17 cell differentiation. In fact, it was shown that IL-27 induces Th17 cell differentiation in the absence of STAT1 and that Th17 cell differentiation is dependent on the ratio of activated STAT3 and STAT1. The ratio induced by IL-6 is more than one, whereas that induced by IL-27 is less than one (178) . Of note is that both STAT3 LOF and STAT1 gain-of-function (GOF) mutations in patients show defects in Th17 cell differentiation (179, 180) . Hyperactivated STAT1-mediated inhibition of Th17 cell differentiation is most likely due to a STAT1-induced upregulation of PD-L1 in naïve T cells (181) , since the PD-L1-PD-1 interaction in naïve T cells impairs Th17 cell differentiation (182) . The critical role of STAT3 for Th17 cell differentiation is also supported by the fact that n-3 fatty acid docosahexaenoic acid and platelet factor 4, both of which induce SOCS3, inhibit Th17 cell differentiation and tumor growth (183, 184) . Further, Zn, which is an essential trace element and affects the immune response and oncogenesis by either pro-inflammatory or anti-inflammatory effects in a context dependent manner (185) , inhibits Th17 cell differentiation through the inhibition of IL-6-induced STAT3 activation (186) .

TGF and IL-6 together induce Th17 cells, while TGF together with IL-2 induces Treg cells. IL-2-activated STAT5 inhibits Th17 cell differentiation (187) , while IL-6 reduces Foxp3 expression, which inhibits RORt-mediated IL-17A promoter activation (188) . Furthermore, opposing regulation of the locus encoding IL-17 through the reciprocal actions of STAT3 and STAT5 suggest the balance between IL-6-STAT3 and IL-2-STAT5 regulates the development of Th17 cells and Treg cells from naïve CD4(+)T cells (189) .

Furthermore, there is Th17/Treg cell plasticity (Fig. 2) . Treg cells when stimulated with IL-6 differentiate into Th17 cells (190) . IL-6 downregulates Foxp3 expression through STAT3 and together with IL-1 induces the genetic reprogramming of Treg cells to express Th17 cell function (191) . Such a conversion of Treg to IL-17-producing Th17 cells is induced by IL-6 derived from synovial fibroblasts in mice suffering collagen-induced arthritis. Th17 cells converted from Treg cells are more potently osteoclastogenic than conventional Th17 cells (192) . The IL-6-induced conversion of Treg cells to Th17 cells is inhibited by miR-125a-5p, which is induced by IL-2 and downregulates the expression of IL-6R and STAT3 in Treg cells (193) . IL-6 further inhibits the suppressive activity of Treg cells. The microbial induction of IL-6 through TLRs inhibits Treg cell activity (194) . IL-6-STAT3 signaling prevents the Treg cell-mediated suppression of Teff cells in patients with psoriasis and multiple sclerosis (MS) (195, 196) .

All evidence supports the idea that the immune system tightly regulates Th17/Treg cell homeostasis through the IL-6-IL-2 axis, and the disturbance of this balance in the presence of TGF causes inflammation and autoimmunity (Fig. 2) . Treg cell dysfunction due to Foxp3 mutation causes a lethal autoimmunity known as immunodysregulation, M a n u s c r i p t polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome (197) , and defects of IL-2 signaling induce severe autoimmunity (198) . Accordingly, low-dose IL-2 therapy for autoimmune and inflammatory diseases is under development (199) . On the other hand, the enhancement of IL-6-STAT3 signaling causes IL-17A-dependent autoimmune arthritis in mice (41,63,66). In line with these findings, several inflammatory and autoimmune diseases, including RA, MS and inflammatory bowel disease show a bias for Th17 cells over Treg cells (163) . Anti-IL-6R therapy in RA restores the homeostasis, suggesting one of possible mechanisms by which the therapy functions (200) .

DCs present antigens to T cells to initiate immune responses and inflammations against infectious pathogens, organ transplants and tumors (201) . Much evidence has accumulated to show that STAT3 functions as an inhibitor for DC differentiation, maturation and antigen-presenting ability, and therefore STAT3 inhibits tumor immunity by interfering with DC functions (25) (Fig. 2) . The requirement of STAT3 for hematopoietic stem cell commitment to the DC lineage has also been shown (202) , but TLR4-induced DC maturation is inhibited by IL-6 (203). Further, IL-6-STAT3 signaling inhibits the LPS-induced maturation of DCs and DC-mediated activation of T cells in vivo (204) . In line with this observation, IL-6-STAT3 signaling reduces intracellular MHC class II levels in DCs by increasing cathepsin S activity (205) . STAT3 activated through TLR9 in myeloid cells inhibits DC maturation and tumor immunity (206) . The enhanced expression of IL-6 in tumor-infiltrating DCs from colorectal cancer patients corelates with a decrease in the expressions of HLA-DR and CD86 on DCs and attenuation of DCs' T cell-stimulating ability (207) . Accordingly, mammary tumorderived exosomes block the differentiation of DCs in vitro through IL-6 (208). Versican is a soluble tumor-derived factor that induces DC dysfunction by upregulating IL-6 and IL-10 receptor signaling (209) .

Classically activated M1 macrophages produce nitric oxide synthase, IL-12 and TNF and promote Th1 cell responses, while activated M2 macrophages produce arginase-1, IL-10 and TGF and relate with the Th2 cell response. M1 macrophages are proinflammatory, while M2 macrophages are anti-inflammatory (210) . Tumor-associated M2 macrophages not only promote tumor progression and metastasis by producing tumor growth factor and angiogenic factors, such as epidermal growth factor (EGF), VEGF and IL-6, but also inhibit tumor immunity by arginase-1, IL-10 and TGF (211) (212) (213) (214) . IL-6 and IL-10 are abundant in tumor microenvironments originated from myeloid cells, fibroblasts and tumor cells, and they further induce M2 macrophage differentiation through STAT3 (215, 216) . Breast cancer-derived exosomes that contain gp130 induce IL-6 production and activate gp130-STAT3 signaling to induce phenotypic changes in bone marrow-derived macrophages toward M2 macrophages (217) .

Myeloid-derived suppressor cells (MDSCs), which are abundant in tumor microenvironments, inhibit T cell activation to suppress tumor immunity by producing IL-10 and TGF (218) . MDSC function is dependent on STAT3 (25). Tumor-derived M a n u s c r i p t Hsp72 mediates the MDSC suppressive activity of tumor growth in a manner dependent on STAT3 activation through the autocrine production of IL-6 (219) (Fig. 2) .

Inhibitors of immune checkpoints, such as inhibitors of CTLA-4 and PD-1 and their ligands, have been shown to be effective to treat several cancers such as melanoma (25,220). PD-L1, which is a ligand of PD-1, is expressed in tumor microenvironments and tumors in a manner dependent on STAT3. For example, the STAT3-dependent expression of PD-L1 in pancreatic carcinoma and head and neck squamous carcinoma was reported (221, 222) . The direct binding of STAT3 to the PD-L1 promoter was also shown (223) . PD-L1 is expressed in non-small cell lung cancer cells through EGF receptor (EGFR)-mediated IL-6-STAT3 activation (224) . Cancer-associated fibroblasts induce PD-L1 in neutrophils in an IL-6-STAT3-dependent manner (225) . In addition, glioblastoma and tumor-associated stromal myofibroblasts induce PD-L1 expression in DCs through IL-6-STAT3 signaling (226, 227) (Fig. 2 ).

All evidence indicates that IL-6-STAT3 signaling determines the homeostasis of Th17 cells and Treg cells. Th17 cells are favored for inflammation and autoimmunity, while Treg cells suppress these responses. Interestingly, the suppressive activity of Treg is observed in several autoimmune diseases (163, 228) . IL-6 makes Teff cells resistant to the suppressive effect of Treg cells (195, 196) . In addition, IL-6-STAT3 signaling induces the conversion of Treg to Th17 cells, which are pro-inflammatory, and induces the differentiation of M2 macrophages and MDSCs, both of which suppress tumor immunity. IL-6 further inhibits DC maturation and upregulates PD-L1 through STAT3 to suppress T cell activation against tumors. Moreover, IL-6 itself is an autocrine and paracrine growth factor as well as a survival factor for a variety of cancers and promotes cancer development and progression by inducing angiogenesis and metastasis. Overall, accumulating evidence supports the intimate relationship of IL-6 with inflammation, autoimmunity and cancer (Fig. 2 ).

Chronic inflammation is often accompanied with autoimmune disease and cancer (2,4,9). Autoimmune diseases are thought to result from a breakdown in self-tolerance and/or dysregulation of immune responses. However, true pathogenic antigens causing the breakdown have not been identified for many autoimmune diseases, including RA and other tissue-specific disorders (229) (230) (231) . This raises the possibility that a breakdown in tolerance to a tissue-specific antigen is not always required for localized autoimmune diseases. Instead, hyper-activation of the immune system to the target tissue may be a consequent event that is initiated by local initiators in non-immune target tissue in a manner dependent on genetic and/or environmental factors (1,47,48,50). This view highlights the importance of local initiators in the target tissue M a n u s c r i p t 12 as a trigger of autoimmunity (49,51,52,57,232). Even in cancer development, it is now known that only 5-10% of all cancers are due to an inherited gene defect, and the remaining 90-95% have their roots in an environment and lifestyle that are intimately related with chronic inflammation (233) . Therefore, rather than the dogma that oncogenesis is intrinsically triggered in pre-neoplastic cells, environmental factors, such as infection, stress, obesity, aging and smoking, each of which can induce chronic inflammation, could be a major cause of oncogenesis (4,6,9,233).

Just after the molecular cloning of IL-6, cardiac myxoma cells were found to produce IL-6 (42). Patients with cardiac myxoma show a variety of autoimmune symptoms, including hypergammaglobulinemia, autoantibodies, and increased acute-phase proteins. These symptoms disappear after surgical resection of the tumor, suggesting the intimate relationship between cardiac myxoma cells and autoimmune symptoms. In addition, it was found that synovial fluid obtained from patients with RA contains high amounts of IL-6 (44,45), and serum IL-6 levels in RA patients correlate with clinical and laboratory indices of the disease (234) . In addition, serum IL-6 levels are increased and correlate with the poor prognosis of multiple myeloma patients (235) . Taking the above together with the fact that IL-6 is a growth factor for plasmacytoma and myeloma (28,37) and the production of IL-6 in Castleman's germinal center (43) suggests that IL-6 is involved in inflammation, autoimmunity and B cell malignancies. Of note is that the pleural effusion cells of patients with pulmonary tubercrosis produce a large amount of factors inducing immunoglobulin production (236); one of the factors was partially purified as a TRF-like factor with similar properties to IL-6 (237). Importantly an intimate relationship between tubercrosis and autoimmunity and B cell malignancies was reported (238) (239) (240) . Furtheremore, pristane and mineral oil, strong inducers of chronic inflammation and later found to induce IL-6 production, develop plasmacytoma, arthritis and autoantibody production in mice (241) (242) (243) (244) (245) . Accordingly, IL-6 transgenic mice develop polyclonal plasmacytosis and monoclonal plasmacytoma in C57BL/6 and BALB/c genetic background, respectively (147, 246) . Moreover, IL-6 induces CRP and fever (247, 248) . All these early studies more than 25 years ago support the idea that IL-6 is involved in diseases (1,80).

In 1994, Kopf et al. showed that IL-6-deficient mice have impaired immune responses against vaccinia virus and Listeria monocytogenes, T-cell-dependent antibody responses against vesicular stomatitis virus, and inflammatory acute-phase responses after tissue damage or infection (148) , confirming the pleiotropic function of IL-6 and its role in immune responses as well as inflammation. By utilizing IL-6-deficient mice, it was shown that IL-6 is required for type II collagen-induced arthritis (249), antigen-induced arthritis (AIA) (250) , EAE (251, 252) , pristane-induced autoantibody production (253) and plasmacytoma (254) , further showing that IL-6 is involved in experimental autoimmune diseases and B cell malignancies. However, experimental autoimmune disease models usually utilize autoantigens in the presence of adjuvants as an inducer of the disease, making it difficult to interpret the results obtained from these experiments in relation to naturally occurring diseases. From this point of view, F759 mice are an ideal murine model of RA, which show an increased activation of STAT3 through gp130 due to the lack of negative regulation exerted by SOCS3 (63,113). Of note is that F759 M a n u s c r i p t 13 mice spontaneously develop IL-6-and CD4(+) T cell-dependent F759 arthritis in a manner dependent on age, supporting the idea that enhanced but dysregulated IL-6-STAT3 signaling is involved in age-related inflammatory autoimmune diseases, such as RA. Furthermore, F759 arthritis is enhanced by human T cell lymphotropic virus 1 (HTLV-1) pX gene, which encodes Tax, a transcriptional trans-activator of NF-B, showing the synergistic effect of STAT3 and NF-B (255) .

Another knock-in mouse (gp130 Y757F/Y757F mice) having the point mutation Y759F in murine gp130 also shows the hyper-activation of STAT3 and develops gastric hyperplasia resembling human early-stage gastric cancer (64, 256) . Further, the mice show a similar expression pattern of STAT3-dependent miR-200 family members with that of early stage gastric cancer patients (142) . Gp130 Y757F/Y757F mice show enhanced colitis-associated tumorigenesis in a manner dependent on the enhanced activation of STAT3 (20). The requirement of IL-6 and STAT3 for activated mutant EGFR-induced lung cancer and colitis-associated cancer has also been demonstrated (18, 257) . Taken together with the fact that the development of pristane or mineral oil-induced plasmacytoma and obesity-related hepatocellular carcinoma (HCC), both of which are related to inflammation, are dependent on IL-6 (254,258), all studies indicate the intimate link between inflammation and tumorigenesis via IL-6-STAT3 signaling.

The reason why different phenotypes are observed between F759 mice and gp130 Y757F/Y757F mice is not known, but the reason could be due to the difference of gp130; the former is human gp130 and the latter is mouse gp130. In fact, it takes about one year for F759 mice to develop arthritis, while gp130 Y757F/Y757F mice show hyperproliferative lesions in the stomach mucosa as early as 6 weeks (256) . It has not yet been reported whether gp130 Y757F/Y757F mice spontaneously develop arthritis as F759 mice do, but AIA, which is also IL-6-dependent, is enhanced in gp130 Y757F/Y757F mice in a manner dependent on STAT3 (259) . Thus, it seems the IL-6-STAT3 axis is involved in inflammation, autoimmunity and cancer and that they are all intimately related to each other.

In line with this notion, there is a correlation between IL-6 and the severity of RA and other inflammatory and autoimmune diseases (3, 260, 261) . In addition, the correlation between IL-6 and the prognosis of 23 different cancer types was demonstrated (262) . Genome-wide association studies (GWAS), meta-analysis, exome analysis and single nucleotide polymorphism (SNP) mapping have associated IL-6, IL-6R and gp130 with inflammatory diseases such as RA and coronary artery disease (263) (264) (265) (266) (267) (268) (269) . It was also reported that IL-6R is associated with asthma and atopic dermatitis (270, 271) . Somatic GOF mutations in gp130 that activate gp130-STAT3 signaling lead to inflammatory hepatocellular tumors (272) . LOF mutations of TRAF3, a negative regulator of IL-6-STAT3 signaling, are observed in B cell lymphoma and multiple myeloma patients (122, 273, 274) . On the other hand, the frequency of a polymorphism at the 5' flanking region of the IL-6 gene that is corelated with lower levels of plasma IL-6 is reduced in systemic-onset juvenile chronic arthritis (275) . Further, a non-conservative SNP in the gp130, Gly148Arg, which has low IL-6 responsiveness, is associated with a decreased risk of myocardial infarction in a hypertensive population (276) . M a n u s c r i p t 14

Although the development of F759 arthritis is dependent on Th17 cells, the F759 mutation is required in non-immune cells but not immune cells, clearly indicating that the interaction between non-immune cells and immune cells is crucial for arthritis development in F759 mice (66,99). In fact, a mutated gp130-mediated excessive production of cytokines and chemokines in non-immune cells in F759 mice is necessary for CD4(+) T cell proliferation, Th17 cell accumulation in the lesion, and the arthritis development (66,99). The effects of non-immune cells in F759 arthritis is explained by the capability of these cells to produce large amounts of chemokines, growth factors and IL-6 under the situation where gp130-mediated STAT3 activation is enhanced. Furthermore, IL-6 and IL-17 or TNF synergistically enhance the production of various pro-inflammatory mediators including IL-6 from non-immune cells in a manner dependent on STAT3 and NF-B (66). The produced IL-6 further induces Th17 cell differentiation through STAT3 in the presence of TGF, IL-1 and IL-23, all of which are rich in inflammatory lesions and tumor microenvironments (164, 166, (169) (170) (171) 174, 175) . Therefore, there is an in vivo positive-feedback amplification loop of IL-6 production via Th17 cell differentiation and their interaction with non-immune cells, such as fibroblasts (41). In addition, the enhanced production of epiregulin and TNF is induced by the activation of IL-6 Amp, and these molecules further activate NF-B alone or STAT3 as well (10). Therefore, amplification of the IL-6-STAT3 axis is augmented by several pathways after the induction of other STAT3 and NF-B activators during inflammation processes (Fig. 3) (41,66) . Of note is that the IL-6 Amp enhances NF-B activity by STAT3 through the interaction of these two molecules. Therefore, the IL-6 Amp amplifies not only IL-6 but also a variety of pro-inflammatory cytokines and growth factors that are targets and/or activators of the NF-B pathway. STAT3 activation is also augmented through enhanced IL-6 production. Consistent with the concept that IL-6 Amp activation in non-immune cells plays a pivotal role in the development of autoimmune diseases, mice devoid of STAT3 or gp130 in non-immune cells like type-1 collagen positive cells are highly resistant to F759 arthritis and EAE (54,66).

The IL-6 Amp could be exerted by several mechanisms. For example, STAT3 prolongs NF-B nuclear retention through acetyltransferase p300-mediated RelA acetylation, thereby interfering with NF-B nuclear export in both cancer cells and tumor-associated hematopoietic cells (277) . The cooperative role of NF-B and STAT3 recruitment to ICAM-1 intronic consensus elements in the invasion and migration of radiation-induced glioma was also reported (278) . STAT3 directly binds to the IL-6 promoter to induce IL-6 gene expression (82,83). In addition, STAT3 activates NF-B through the direct induction of miR-21 and miR-181b-1, leading to IL-6 gene expression (90). NF-B also increases IL-6 levels by inhibiting let-7 expression (89).

As described above, the IL-6 Amp is a mechanism by which the regional production of a variety of cytokines and growth factors are augmented through the interaction between A c c e p t e d M a n u s c r i p t 15 NF-B and STAT3, both of which are activated not only in inflammatory lesions but also in tumor microenvironments and neoplastic tumor cells. Furthermore, NFB and STAT3 play crucial roles in cancer development and progression (19, 25, 67, 279) . Thus, the IL-6 Amp plays a crucial role in not only chronic inflammatory and autoimmune diseases but also cancer. In fact, a comparative analysis between GWAS data and the targets or regulatory genes of the IL-6 Amp revealed that 202 out of 1700 screened genes show over 490 indications of association not only with autoimmune diseases but also with metabolic syndromes, neurodegenerative diseases and other chronic inflammatory diseases, including RA, lupus, pancreatitis, thyroiditis/Graves' diseases, type 1 diabetes (T1D) and type 2 diabetes (T2D), MS, cardiovascular diseases/atherosclerosis/systemic sclerosis, Alzheimer's disease/hippocampal atrophy, pulmonary disease/asthma/cystic fibrosis, hepatitis, inflammatory bowel disease/colitis, stroke and nephropathy/glomerulonephritis (10). Furthermore, many cancer-associated genes were identified as regulators or target genes of the IL-6 Amp (11). Ingenuity Pathways Analysis (IPA) showed that these genes are related with multiple biologic processes, such as cell development, cell cycle, transport, signal transduction, adhesion, cell movement, chemotaxis, immune response, angiogenesis and metabolic process. Moreover, the IL-6 Amp is related with various types of cancer, including hematologic malignancies, tumors in lung, and colorectal/intestinal, urinary/bladder/vulvar, breast, stomach and liver cancers (11).

The IL-6 Amp, which is activated not only in non-immune cells such as fibroblasts and endothelial cells but also in grafted organs and tumor cells, acts as a linker between these cells and immune cells by attracting immune cells through the production of a variety of chemokines. Accumulated immune cells interact with non-immune cells in inflammatory lesions and tumor microenvironments as well as with tumor cells to further enhance the IL-6 Amp by producing not only IL-6 but also a variety of IL-6 Amp stimulators such as IL-17, TNF, IL-1 and epiregulin. Target molecules of the IL-6 Amp include EGFR, c-Myc, Pim1, VEGF, hypoxia-inducible factor 1-alpha (HIF1-), matrix MMPs and many pro-inflammatory cytokines and growth factors involved in cell survival, proliferation, angiogenesis and metastasis (10,11) (Fig. 3) .

In 1964, Boyden pointed out the importance of local initiators such as injury or infection as triggers of inflammation followed by the destruction of the target tissues (47). Decades later, Wilkin proposed the primary lesion theory, in which a primary lesion triggers autoimmunity, rather than the popular view, which held the primary cause of autoimmunity was the breakdown of self-tolerance (48).

Patients with RA show a variety of symptoms, including polyclonal plasmacytosis accompanied by the production of rheumatoid factor, enhanced bone resorption, and increases in the amount of acute-phase proteins, agalactosyl IgG and platelet numbers. None of these phenotypes at first glance appear related to each other, suggesting that complex factors are involved in RA. However, the pleiotropic nature of IL-6, which induces B cell differentiation with immunoglobulin production (27), osteoclast activation A c c e p t e d M a n u s c r i p t 16 (280, 281) , the production of acute-phase proteins (39,40), the increase of agalactosyl immunoglobulin (282) and megakaryocyte differentiation (281, 283, 284) , suggested an intimate relationship between IL-6 and RA. Assuming that the same cause can induce both RA and IL-6 expression, such an intimate relationship could be explained. This possibility led to a working hypothesis (1,46), the updated version of which is called the local initiation model (Fig. 4) . In this model, NF-B and STAT3 are activated by a variety of local initiators, including injury, infection, stressors, age-related events in senescent cells and oncogenic mutation in pre-neoplastic cells, leading to the activation of the IL-6 Amp in non-immune cells, such as fibroblasts, epithelial cells, endothelial cells and adipocytes. The IL-6 Amp enhances the production of a variety of proinflammatory cytokines and chemokines, resulting in the recruitment of immune cells, such as activated T cells into the lesion. The interaction between immune cells, in particularly activated T cells further strengthens the IL-6 Amp. The IL-6 Amp can become dysregulated depending on the genetic background and other factors including local initiators, leading to inflammatory diseases and autoimmune diseases. Because initial events occur in non-immune cells or tissues, this model strengthens the importance of both local initiators in the target tissue and the interaction between nonimmune and immune systems in the disease onset and progression. The local initiation model is similar to the primary lesion theory proposed by Wilkin (48), but the former clearly shows the key role of transcription factors, such as NF-B and STAT3, which can simultaneously induce multiple actions and be activated by a variety of local initiators. Therefore, the local initiation model could be applied not only to chronic inflammatory diseases and autoimmune diseases, but also to age-related diseases and cancer (Fig. 4) .

One clear piece of evidence supporting the local initiation model has been obtained from F759 mice. F759 mice bred by mating T cell receptor transgenic mice and Rag2-KO mice to express only one T cell receptor on CD4(+) T cells still develop arthritis. These results suggest even T cell-dependent tissue-specific autoimmune diseases do not necessarily require antigen-specific T cells (52). The question is, what determines the tissue specificity of the autoimmune disease without tissue-specific CD4(+) T cells? Murakami et al. demonstrated that local initiator such as microbleeding induce the accumulation of T cells in the joints through CCL20 production(52). The disease induction requires IL-17A production by transferred T cells, IL-6 and CCL20 expression and STAT3 signaling in type I collagen-expressing cells. This is consistent with the IL-6 Amp being involved in the disease.

Persistent local initiator activity, such as chronic infections, with or without genetic factors leads to chronic activation of the IL-6 Amp. This effect induces the manifestation of inflammatory diseases and autoimmune diseases (232) . This scenario highlights the importance of local initiators and supports the local initiation model (Fig. 4) . It is also consistent with the fact that many chronic inflammatory diseases are dependent on aging and accompanied by the activation of polyclonal T cells and increase of IL-6 (285).

Local initiators activating the IL-6 Amp in chronic inflammation A variety of stressors, such as pain, light and gravity are sensed by a sensorysympathetic neural network. Neuroinflammation is associated with the invasion of various immune cells in the central nervous system (CNS) followed by the dysregulation of homeostasis in the brain and spinal cord. However, the CNS is protected by the blood-brain barrier, which tightly limits the traffic of substances and immune cells from the blood. In an adoptive transfer model of EAE using myelin-specific autoreactive CD4(+) T cells, it was found that the initial invasion site of these cells is determined by specific neural activation through the sensory-sympathetic pathway stimulated by gravity (54). This neural pathway, which is now called the gateway reflex (286, 287) , activates the IL-6 Amp through beta-adrenergic receptors in the dorsal vessels of the 5th lumbar cord, allowing for autoreactive T cell accumulation and disease onset (54). Further, pain sensation induces a relapse of EAE by activating the IL-6 Amp through another sensory-sympathetic neural network (55). Consistent with this, it was reported that adrenergic receptor stimulation not only activates STAT3 in an ovarian cancer cell line (288) but also enhances the IL-6 production that is induced by IL-1, a NF-B activator in cardiomyocytes, to induce cardiac hypertrophy (289) . Additionally, it was shown that acute stress induces a systemic increase of IL-6 secreted from brown adipocytes in a beta-3-adrenergic-receptor-dependent manner in mouse models (290) .

These studies provide evidence supporting the claim that a variety of stressors, such as gravity and pain, act as local initiators through specific neural pathways, resulting in activation of the IL-6 Amp, linking inflammation and autoimmunity and possibly affecting cancer development and progression.

Age-related changes in senescent cells also act as local initiators. Senescent fibroblasts secrete high levels of several MMPs, EGF and inflammatory cytokines, resembling fibroblasts undergoing a wound response or associations with cancer. Of note, the local low-grade inflammation that characterizes aging is triggered by senescent cells and is intimately related to age-related diseases such as cardiovascular diseases and cancer (5, 291, 292) . It might also be associated with the cytokine storm in COVID-19 (293, 294) . These mediators maintain and propagate the senescence process to neighboring cells and then recruit immune cells to clear the senescent cells. In this scenario, Campisi proposed a model in which senescent cells by themselves contribute to the disruption of normal tissues through the production of degradative enzymes as well as inflammatory cytokines, while senescent cells help pre-neoplastic mutated cells to proliferate by producing inflammatory cytokines(5). NF-B-regulated and C/EBP-regulated cytokines such as IL-6 and CXCR2-binding chemokines including IL-8, which are produced by senescent cells, play crucial roles in the senescence process (7,8). IL-6-STAT3-PIM-1 signaling is involved in cytokine-induced senescence (295) . Importantly, senescent cells and tissues contribute to age-related pathologies including cancer by producing inflammatory cytokines such as IL-6, which act as autocrine and paracrine factors (7). Consistently, IL-6 levels increase with age (296, 297) . Concerning age-related diseases, senescent cells themselves are critically involved in T1D and T2D, and the deletion of senescent beta cells prevents diabetes (57,298), indicating that even in T1D in which M a n u s c r i p t tissue-specific T cells are involved (299) (300) (301) , local initiators originating from senescent beta cells play critical roles. This process is consistent with the idea that the primary cause of T1D may be a senescent-induced local initiator that can activate the IL-6 Amp rather than the breakdown of self-tolerance.

Obesity causes chronic low-grade inflammation and is closely related with chronic inflammatory diseases, such as cardiovascular diseases and T2D and some cancers, such as breast, liver and colon cancers (233, (302) (303) (304) . The enlargement of adipose tissue in obesity induces mechanical stress, ER stress and hypoxia in adipocytes, resulting in the release of free fatty acids (FFA) and inflammatory cytokines such as IL-6 and TNF and chemokines (303) (304) (305) , suggesting activation of the IL-6 Amp. Consistently, these events recruit macrophages, which further produce IL-6 and TNF, major players involved in obesity-induced low-grade inflammation and cancer development (303, 304) . Shi et al. showed that FFA activates TLR4 signaling and that mice lacking TLR4 are partially protected against high fat diet-induced insulin resistance (306) . In line with these findings, FFA activates NF-B through TLR4, leading to the expression of monocyte chemotactic protein-1 (MCP-1) to recruit macrophages, which further produce IL-6 and TNF (307, 308) . IL-6-STAT3 signaling in adipocytes is shown to be involved in adipocyte-induced EMT in breast cancer cells (23) and obesity-promoted HCC (258) . Lysophospholipid sphingosine-1-phosphate (S1P), a lipid metabolite activates STAT3 through its G protein-coupled receptor, S1P receptor-1 (309). Intracellular S1P induces IL-6 production through NF-B activation, resulting in the activation of both STAT3 and NF-B, major players of the IL-6 Amp. This process is critically involved in colitisassociated cancer (310) . These findings support the idea that obesity-induced mechanical and/or ER stress and lipid metabolites act as local initiators in the target tissue to trigger chronic activation of the IL-6 Amp.

Pre-neoplastic cells or cancer cells by themselves act as local initiators much like senescent cells do. Either or both of STAT3 and NF-B are activated in a variety of tumors, including lung, breast, pancreatic and prostate cancers (67). Additionally, either or both are activated in cells transformed with HTLV-1 (311), v-src (312), abl (313), bcrabl or v-eyk (314). K-RAS mutation is often observed in many cancers, such as lung cancer and pancreatic cancer. Mutated K-RAS activates NF-B in a mouse model of lung cancer (315) , and the K-RAS-induced activation of NF-B is required for pancreatic cancer development (316) , which depends on IL-6 trans-signaling-mediated STAT3 activation (317) . Mesothelin (MSLN) is up-regulated following K-RAS, p53 and p16 mutations in pancreatic cancer (318) . MSLN is also suggested to be involved in the progression of breast cancer, ovarian cancer and pancreatic cancer. It confers pancreatic cancer cell resistance to TNF-induced apoptosis through NF-B activation and the enhanced expression of IL-6 (319). MSLN also promotes pancreatic cancer cell proliferation through autocrine IL-6 trans-signaling (320) . Similarly, activated mutant EGFR in lung cancer induces IL-6 gene expression to activate constitutive IL-6-STAT3 signaling in a paracrine and autocrine manner (257) . HER2 overexpression occurs in M a n u s c r i p t approximately 25% of breast cancers. Its expression in breast cancer activates an IL-6 autocrine signaling loop to activate STAT3, which is critical for tumorigenesis (321) . The loss of p53 alone is insufficient to initiate intestinal tumorigenesis but markedly enhances carcinogen-induced tumor incidence, the progression of which is associated with increased intestinal permeability, causing the formation of a NF-B-dependent inflammatory microenvironment (322) . Another oncogenic molecule, BRAF E600 , induces IL-6 and IL-1, a NF-B activator, through C/EBP (7).

All the above results are in line with cancer cells activating the IL-6 Amp through the direct or indirect activation of NF-B and STAT3, likely resulting in the recruitment of Th17 cells and/or myeloid cells to further enhance the IL-6 Amp. RANTES and MCP-1 secreted by tumor cells and tumor-derived fibroblasts mediate the recruitment of Th17 cells (159) . Exosomal miR-1247-3p secreted by hepatocellular carcinoma activates beta1integrin-NF-B signaling in fibroblasts, resulting in the production of pro-inflammatory cytokines, including IL-6 and IL-8 (323) . The IL-6 Amp at the leading edge could play a critical role in tumor progression. Indeed, Chang et al. showed that IL-6-STAT3 signaling is increased at the leading edge of breast tumors to promote MDSC recruitment, angiogenesis, fibroblast infiltration and metastases (83).

Infection is a local initiator that triggers and maintains inflammation, leading to chronic inflammatory diseases and cancer. For the initial detection of microbes, the immune system utilizes pattern-recognition receptors (PRRs), such as TLRs to activate MyD88-dependent signaling and ultimately activate NF-B (324) . In addition to NF-B activation, TLRs such as TLR2, TLR4, TLR7 and TLR9 activate STAT3 (206, 325) . TLR stimulation also induces IL-6 production and other pro-inflammatory cytokines through NF-B, leading to activation of the IL-6 Amp. Therefore, infection is one trigger of the IL-6 Amp. Indeed, a human colonic bacterium, enterotoxigenic Bacteroides fragilis (ETBF)-derived toxin, which triggers colitis and induces colonic tumors in mice, activates the STAT3 and Th17 response (326) . Helicobacter pylori, which induces gastritis and is related to gastric cancer, activates STAT3 in epithelial cells (327 Cytokine storm, uncontrolled acute inflammation COVID-19, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is now a pandemic. The life-threating phenotype of COVID-19 is severe acute respiratory distress syndrome (ARDS) (333) . ARDS is a lethal syndrome induced by mechanical injury and infection such as pneumonia, sepsis and trauma (334) . ARDS in COVID-19 is considered the result of cytokine storm (12-17), resembling the disease caused by SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV) (335) . Cytokine storm is uncontrolled and rapidly progressing inflammation accompanied by the massive production of pro-inflammatory cytokines, chemokines and growth factors. M a n u s c r i p t 20 Consistent with the notion that severe COVID-19 is a cytokine storm syndrome (12-17,336), the severity of COVID-19 is associated with an increased level of inflammatory cytokines, such as IL-6, granulocyte macrophage-colony stimulating factor (GM-CSF) and TNF (333, 337) . Among the elevated inflammatory mediators, the blood IL-6 level is highly correlated with the disease mortality (293, 338) and predicts the need for mechanical ventilation (339) . Notably, IL-6 and TNF serum levels are shown to be significant predictors of disease severity and death (340) .

SARS-CoV-1 and MERS-CoV activate NF-B in a manner dependent on MyD88 through PRRs, such as retinoic acid-inducible gene I protein (RIG-I) and melanoma differentiation-associated protein 5 (MDA5), leading to the activation of a variety of proinflammatory cytokines, including IL-6, TNF, IL-8 and CC-chemokine ligand 2 (CCL2) (335) . In addition to this PRR-mediated activation of NF-B, the nucleocapsid protein of SARS-CoV-1 activates IL-6 expression through NF-B by facilitating the translocation of NF-B from the cytosol to the nucleus (341) . Since SARS-CoV-2 uses angiotensin converting enzyme (ACE )2 as a receptor (342, 343) , it is speculated that SARS-CoV-2 induces pro-inflammatory cytokines through angiotensin II (AngII)/angiotensin type 1 receptor (AT1R) (15) as SARS-CoV-1 does (344) (345) (346) .

The AngII-AT1R axis activates the NF-B pathway through various growth factors and pro-inflammatory cytokines (347, 348) . This axis activates ADAM17, which generates the mature form of EGFR ligand and TNFtwo NF-B stimulators (346) . Furthermore, ADAM17 increases sIL-6Rwhich activates STAT3 through gp130 on a variety of nonimmune cells including fibroblasts, endothelial cells and epithelial cells (33,96). Therefore, it is likely that the AngII-AT1R axis is involved in the ARDS induced by SARS-CoV-2 infection (15), which is like SARS-CoV-1-induced ARDS in a mouse model (344) .

Therefore, SARS-CoV-1 and SARS-CoV-2 infection activate both NF-B and STAT3, key elements of the IL-6 Amp, to cause cytokine storm (12, 13, 15, 349, 350) . Since an activated IL-6 Amp enhances the production of chemokines to recruit lymphoid cells and myeloid cells including Th17 cells in the lesion, the IL-6 Amp could be further enhanced (66).

Cytokine storm also occurs in chimeric antigen receptor T cell (CAR-T) treatment, which is used to treat leukemia. It is triggered by the activation of CAR-T cells that recognize cognate antigens expressed by tumor cells, leading to the release of cytokines and chemokines, including IL-6 in parallel with the release of pro-inflammatory cytokines and chemokines by monocytes and/or macrophages (351, 352) . IL-1 and IL-6 are involved in the lethal cytokine storm sometimes seen in CAR-T treatment (353, 354) .

The massive cell death commonly observed in cytokine storm, regardless of the inducer type, activates damage-associated molecular pattern (DAMP) receptor-mediated signaling pathways and or TLR-mediated ones. These events further induce proinflammatory cytokines including IL-6 through NF-B activation.

Taking together all the evidence described above, a possible mechanism of SARS-CoV-1-and SARS-CoV-2-induced cytokine storm is illustrated in Fig.5 . This model could be applied to ARDS induced by other causes. ARDS with a cytokine storm occurs in viral infections such as MERS-CoV, influenza virus and sepsis. Furthermore, it also occurs due to lung damage caused by gastric acid or inappropriate operation of a ventilator, like aspiration pneumonia (334) . The AngII-AT1R signaling system plays an important role not only in pneumonia but also in ARDS model mice (345) , indicating that lung injury itself activates the AngII-AT1R signaling. Macrophage activation via TLR4, a type of PRR, is also involved in gastric acid-induced ARDS and mouse ARDS models induced by SARS-CoV-1 or influenza virus H5N1 (355) . Furthermore, it has been shown that ARDS and renal dysfunction induced in a sepsis rat model are suppressed by anti-IL-6 receptor antibody through the suppression of NF-B activation (356) . Interestingly, ACE1 gene polymorphisms are involved in the development and severity of ARDS (357) . Furthermore, the ACE1 II genotype is protective against COVID-19 as compared to the ACE1 DD genotype (358) , and serum levels of ACE1 are higher in the DD genotype compared with the II genotype (359) .

Consistent with animal models, it was reported that AngII-AT1R axis inhibitors may be beneficial for COVID-19 patients (360) (361) (362) (363) to decrease serum IL-6 levels (360) . The anti-IL-6R antibody tocilizumab is effective at treating patients with CAR-T-induced cytokine release syndrome (CRS) (352, 364) and is being considered for treating ARDS in COVID-19 patients (365) (366) (367) (368) . Baricitinib, an inhibitor of JAK1 and JAK2, is reported to prevent COVID-19 severity followed by lowering IL-6 and TNFlevels (369) . In addition, dexamethasone reduces the death rate of patients with severe COVID-19 (370) .

Of note, aging, obesity and inflammation-related diseases such as diabetes and cardiovascular diseases have been shown to be risk factors for the severity of COVID-19 (293, (371) (372) (373) . As discussed in this manuscript, these risk factors are all associated with chronic inflammation, which could decrease the threshold of the activation of the IL-6 Amp to induce cytokine storm.

At the time of its discovery in 1986, IL-6 was considered just one of many cytokines. It has since been clarified that IL-6 is a critical factor in inflammation, autoimmunity and cancer, and its inhibitors are used as therapeutic agents for several diseases already, with the potential of being expanded to more in the future. The anti-IL-6R antibodies tocilizumab and sarilumab are used to treat RA, Castleman's disease and CAR-Tinduced CRS (71-75,352,364) and have promise for treating the severe form of COVID-19 (365) (366) (367) . Other inhibitors against the IL-6-STAT3 signaling pathway are under development (19,21,24-26,76,374 ).

One possible explanation for why inhibiting IL-6 activity is effective against inflammation-related diseases, in spite of the many cytokines involved, is that in inflammation IL-6 is the major stimulator of STAT3, which plays important roles in A c c e p t e d M a n u s c r i p t 22 inflammation and oncogenesis together with NF-B, which expresses IL-6 as a target. Therefore, NF-B and STAT3 for the basis of an amplification mechanism, the IL-6 Amp, which produces pro-inflammatory molecules, including IL-6 itself and other proinflammatory cytokines and growth factors. A variety of local initiators, such as infection, stressors, injury, senescence, obesity, pre-neoplastic mutation, cell death and smoking can activate the IL-6 Amp, which mediates the interaction between nonimmune cells and immune cells, leading to the manifestation of inflammatory and autoimmune diseases and cancer. These observations have led to a strategy targeting the IL-6-STAT3 signaling axis to treat related diseases.

However, many questions remain. One of the reasons why IL-6 is a key cytokine in inflammation is that it has a wide range of target cells due to its trans-signaling mechanism. IL-6 usually acts on lymphoid and myeloid immune cells expressing both IL-6R and gp130, but it acts on a wide range of non-immune cells as well, including fibroblasts and endothelial cells that express gp130 during inflammation. For this action, sIL-6Ris required. Therefore, more study of the mechanism by which sIL-6R is generated is required to understand inflammation and develop therapeutics (96). Another question concerns the mechanism of the synergistic action of STAT3 and NF-B. STAT3 and NF-B are involved in a wide range of inflammatory diseases and cancer development and, more importantly, their interaction is central to activation of the IL-6 Amp. More study on the synergistic activation would also open the way to new therapeutics.

Since the IL-6 Amp is deeply involved in uncontrolled inflammation, it is critical to elucidate the genetic and environmental factors that destabilize it. Defects in the negative feedback mechanism mediated by SOCS3 observed in F759 mice is one factor worth investigating. So too are the transcriptional factors and microRNAs that cause STAT3 and NF-B to indirectly interact .

To realize a healthy aging society, it is crucial to prevent and cure age-related diseases. The list of diseases is long and includes autoimmune diseases, diabetes, cardiovascular diseases, dementia, pneumonia and cancer, all of which are related to uncontrolled inflammation. Uncontrolled inflammation is triggered by a variety of local initiators, including senescence, obesity, stressors through regional neural pathways, and infection through activation of the IL-6 Amp. More research on the effects of each initiator, either individually or synergistically with other initiators, on the inflammatory process and the IL-6 Amp would give deeper insights on inflammation, its prevention and cures.

Inflammatory diseases, autoimmune diseases and cancer are induced by complex interactions between non-immune cells and immune cells via the IL-6 Amp. Therefore, the expressions and/or functions of IL-6 Amp-related molecules could be used to predict diseases initiated by local initiators. However, current knowledge is insufficient for predicting the end stage or detailed process of the disease. Furthermore, there are many pro-inflammatory molecules that determine the state of the IL-6 Amp as well as inflammation. The modes of interactions between these molecules too require more study. Improvements in detection technology and systems biology research for age-and M a n u s c r i p t 23 inflammation-related diseases driven by artificial intelligence (AI) would be helpful (375) .

Several inhibitors of IL-6 are now clinically used, but in order to develop small peptides or compounds with higher specificity and efficacy against diseases, high-resolution structural analysis of the ligand-receptor complex is needed. We can study the steady state of molecular interactions at the molecular level, but it is difficult to analyze in real time the dynamic changes of the molecular state of the receptor complexes and signaling molecules. Here, quantum life sciences in the field of inflammation will be helpful (376, 377) .

A c c e p t e d M a n u s c r i p t The phosphorylation of tyrosine 759 of gp130 is required for the gp130-mediated ERK-MAPK pathway via SHP2 and GAB adaptor molecules and essential for the SOCS3mediated negative feedback loop. The distal four tyrosine residues of gp130 (Y767, Y814, Y905, and Y915) form a YXXQ motif, which is required for STAT3 activation. The YAP-Notch pathway is triggered by Yes. TRAF is associated with gp130 and inhibits the STAT3 signaling pathway. MiR-135a and miR-337-3p downregulate JAK2 and STAT3, respectively. PIAS directly inhibits STAT3. All amino acid positions are of human gp130. (B) Three modes of gp130-mediated signaling. IL-6 acts on cells expressing both IL-6Rα and gp130 (classical signaling). The complex of IL-6 and sIL-6Rα acts like a novel cytokine on cells expressing only gp130 (trans-signaling). In the trans-presentation mode, IL-6 bound to IL-6Rα expressed on one type of cell acts on another cell type expressing gp130. STAT3 activators (e.g. IL-6) and NF-B activators (e.g. IL-17 or TNF synergistically enhance the production of various pro-inflammatory mediators including IL-6 from nonimmune cells in a manner dependent on STAT3 and NF-B. This amplification mechanism is called the IL-6 amplifier (IL-6 Amp). The IL-6 Amp recruits immune cells such as activated T cells into the lesion by chemokines. The interaction between immune cells and non-immune cells further strengthens the IL-6 Amp. The IL-6 Amp enhances the expression of many genes involved in cell proliferation, survival, movement, inflammation, angiogenesis and so on.

A variety of local initiators, such as infection, injury, stressor through neural networks, senescence, obesity, smoking and oncogenic mutations activate both STAT3 and NF-B, leading to activation of the IL-6 Amp in non-immune cells such as fibroblasts, epithelial cells, endothelial cells and adipocytes. The IL-6 Amp amplifies the production of IL-6 M a n u s c r i p t 25 and other pro-inflammatory cytokines and growth factors. Chemokines produced by the IL-6 Amp recruit immune cells such as activated T cells to the lesion to interact with non-immune cells, leading to further activation of the IL-6 Amp. The IL-6 Amp becomes dysregulated depending on the genetic background and or other factors including the properties of local initiators, leading to chronic inflammatory diseases, autoimmune diseases and cancer. Because SARS-CoV-1/2 utilizes ACE2 as a receptor, virus infection decreases the cell surface expression of ACE2, which is a peptidase of AngII, resulting in an increase of AngII. In addition, virus-induced lung injury activates ACE1, further increasing serum angiotensin 2 levels. As a result, AT1R-mediated signaling is enhanced. In turn, so too is the inflammatory response, including TNF and sIL-6R via ADAM17 activation. Virus infection, itself activates signaling through pattern-recognition receptors (PRRs). Furthermore, virus-induced massive cell death can activate DAMP receptor-mediated signaling pathways. Moreover, virus infection activates and or recruits lymphoid cells and myeloid cells in the lesion. All these events synergistically activate the IL-6 Amp through the interaction of STAT3 and NF-B, leading to cytokine storm. M a n u s c r i p t M a n u s c r i p t 33 M a n u s c r i p t 35 M a n u s c r i p t M a n u s c r i p t

The JAK-STAT pathway at twenty

Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis

Differentiation and growth arrest signals are generated through the cytoplasmic region of gp130 that is essential for Stat3 activation

Gab1 acts as an adapter molecule linking the cytokine receptor gp130 to ERK mitogenactivated protein kinase

Gab-family adapter proteins act downstream of cytokine and growth factor receptors and T-and B-cell antigen receptors

A gp130-Src-YAP module links inflammation to epithelial regeneration

IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland

STAT3 orchestrates contradictory signals in cytokine-induced G1 to S cell-cycle transition

Defective gp130-mediated signal transducer and activator of transcription (STAT) signaling results in degenerative joint disease, gastrointestinal ulceration, and failure of uterine implantation

Imbalanced gp130-dependent signaling in macrophages alters macrophage colony-stimulating factor responsiveness via regulation of c-fms expression

Dissection of signaling cascades through gp130 in vivo: reciprocal roles for STAT3-and SHP2-mediated signals in immune responses

Protein tyrosine phosphatase 2 (SHP-2) moderates signaling by gp130 but is not required for the induction of acute-phase plasma protein genes in hepatic cells

Activation of the protein tyrosine phosphatase SHP2 via the interleukin-6 signal transducing receptor protein gp130 requires tyrosine kinase Jak1 and limits acute-phase protein expression

SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6 signaling through gp130

Negative regulation of gp130 signalling mediated through tyrosine-757 is not dependent on the recruitment of SHP2

Suppressors of cytokine signaling and immunity

Suppressor of cytokine signaling-3 preferentially binds to the SHP-2-binding site on the shared cytokine receptor subunit gp130

SOCS3 exerts its inhibitory function on interleukin-6 signal transduction through the SHP2 recruitment site of gp130

The adaptor TRAF5 limits the differentiation of inflammatory CD4(+) T cells by antagonizing signaling via the receptor for IL-6

The adaptor protein TRAF3 inhibits interleukin-6 receptor signaling in B cells to limit plasma cell development

Regulation of JAK2 by miR-135a: prognostic impact in classic Hodgkin lymphoma

miR-337-3p and its targets STAT3 and RAP1A modulate taxane sensitivity in non-small cell lung cancers

Specific inhibition of Stat3 signal transduction by PIAS3

STAT3 is required for the gp130-mediated full activation of the c-myc gene

Synergistic roles for Pim-1 and c-Myc in STAT3-mediated cell cycle progression and antiapoptosis

IL-6 stimulates STAT3 and Pim-1 kinase in pancreatic cancer cell lines

PIM-1 contributes to the malignancy of pancreatic cancer and displays diagnostic and prognostic value

PIM1 is responsible for IL-6-induced breast cancer cell EMT and stemness via c-myc activation

Interleukin-6 induces an epithelialmesenchymal transition phenotype in human breast cancer cells

IL-6 promotes head and neck tumor metastasis by inducing epithelialmesenchymal transition via the JAK-STAT3-SNAIL signaling pathway

Constitutively active Stat3 enhances neu-mediated migration and metastasis in mammary tumors via upregulation of Cten

Progenitor/stem cells give rise to liver cancer due to aberrant TGF-beta and IL-6 signaling

RhoC regulates cancer stem cells in head and neck squamous cell carcinoma by overexpressing IL-6 and phosphorylation of STAT3

Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis

Interleukin-6 promotes cervical tumor growth by VEGFdependent angiogenesis via a STAT3 pathway

Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways

Interleukin-6 induces both cell growth and VEGF production in malignant mesotheliomas

Autocrine IL-6-induced Stat3 activation contributes to the pathogenesis of lung adenocarcinoma and malignant pleural effusion

Interleukin-6 dependent survival of multiple myeloma cells involves the Stat3-mediated induction of microRNA-21 through a highly conserved enhancer

Clinical Utility of a STAT3-Regulated miRNA-200 Family Signature with Prognostic Potential in Early Gastric Cancer

The essential role of B cell stimulatory factor 2 (BSF-2/IL-6) for the terminal differentiation of B cells

Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6

Plasma cell survival is mediated by synergistic effects of cytokines and adhesiondependent signals

Follicular Helper T Cells

IgG1 plasmacytosis in interleukin 6 transgenic mice

Impaired immune and acute-phase responses in interleukin-6-deficient mice

The role of interleukin-6 in mucosal IgA antibody responses in vivo

Critical role for Stat3 in T-dependent terminal differentiation of IgG B cells

STAT3-mediated up-regulation of BLIMP1 Is coordinated with BCL6 down-regulation to control human plasma cell differentiation

Impaired antibody responses in the hyperimmunoglobulin E syndrome

Heterozygous signal transducer and activator of transcription 3 mutations in hyper-IgE syndrome result in altered B-cell maturation

STAT-3 activation by differential cytokines is critical for human in vivo-generated plasma cell survival and Ig secretion

Interleukin (IL)-6 directs the differentiation of IL-4-producing CD4+ T cells

Soluble IL6R Expressed by Myeloid Cells Reduces Tumor-Specific Th1 Differentiation and Drives Tumor Progression

IL-17 and Th17 Cells

Tumor microenvironments direct the recruitment and expansion of human Th17 cells

Th17 Cells in Protection from Tumor or Promotion of Tumor Progression

Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses

Targeting Treg cells in cancer immunotherapy

When worlds collide: Th17 and Treg cells in cancer and autoimmunity

TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells

The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells

Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells

IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells

The influence of excessive IL-6 production in vivo on the development and function of Foxp3+ regulatory T cells

Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells

Development, cytokine profile and function of human interleukin 17-producing helper T cells

Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling

The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo

The MicroRNA-183-96-182 Cluster Promotes T Helper 17 Cell Pathogenicity by Negatively Regulating Transcription Factor Foxo1 Expression

IL-6-gp130-STAT3 in T cells directs the development of IL-17+ Th with a minimum effect on that of Treg in the steady state

Cutting edge: An in vivo requirement for STAT3 signaling in TH17 development and TH17-dependent autoimmunity

Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system

IL-27 controls the development of inducible regulatory T cells and Th17 cells via differential effects on STAT1

IL-27 Induces Th17 Differentiation in the Absence of STAT1 Signaling

Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome

Gainof-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis

PD-L1 up-regulation restrains Th17 cell differentiation in STAT3 loss-and STAT1 gain-of-function patients

Interleukin-27 priming of T cells controls IL-17 production in trans via induction of the ligand PD-L1

SOCS3 transactivation by PPARgamma prevents IL-17-driven cancer growth

Platelet factor 4 inhibits IL-17/Stat3 pathway via upregulation of SOCS3 expression in melanoma

Zinc homeostasis and signaling in health and diseases: Zinc signaling

Zinc suppresses Th17 development via inhibition of STAT3 activation

Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation

Foxp3 inhibits RORgammat-mediated IL-17A mRNA transcription through direct interaction with RORgammat

Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5

Cutting edge: regulatory T cells induce CD4+CD25-Foxp3-T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-beta

Molecular antagonism and plasticity of regulatory and inflammatory T cell programs

Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis

MiR-125a-5p Decreases the Sensitivity of Treg cells Toward IL-6-Mediated Conversion by Inhibiting IL-6R and STAT3 Expression

Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells

IL-6 signaling in psoriasis prevents immune suppression by regulatory T cells

In active relapsing-remitting multiple sclerosis, effector T cell resistance to adaptive T(regs) involves IL-6-mediated signaling

IPEX as a result of mutations in FOXP3

Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor beta

The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases

Brief report: inhibition of interleukin-6 function corrects Th17/Treg cell imbalance in patients with rheumatoid arthritis

The dendritic cell system and its role in immunogenicity

STAT3 is required for Flt3L-dependent dendritic cell differentiation

Novel immunosuppressive properties of interleukin-6 in dendritic cells: inhibition of NF-kappaB binding activity and CCR7 expression

IL-6 regulates in vivo dendritic cell differentiation through STAT3 activation

IL-6-STAT3 controls intracellular MHC class II alphabeta dimer level through cathepsin S activity in dendritic cells

Toll-like receptor 9 activation of signal transducer and activator of transcription 3 constrains its agonist-based immunotherapy

IL-6 down-regulates HLA class II expression and IL-12 production of human dendritic cells to impair activation of antigen-specific CD4(+) T cells

Tumor exosomes inhibit differentiation of bone marrow dendritic cells

Tolllike Receptor 2 Activation Promotes Tumor Dendritic Cell Dysfunction by Regulating IL-6 and IL-10 Receptor Signaling

Alternative activation of macrophages: an immunologic functional perspective

Tumourassociated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy

Distinct role of macrophages in different tumor microenvironments

From Monocytes to M1/M2 Macrophages: Phenotypical vs

Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells

Regulation of immunophenotype modulation of monocytesmacrophages from M1 into M2 by prostate cancer cell-culture supernatant via transcription factor STAT3

Interleukin 6 induces M2 macrophage differentiation by STAT3 activation that correlates with gastric cancer progression

Breast Cancer-Derived Exosomes Alter Macrophage Polarization via gp130/STAT3 Signaling

The terminology issue for myeloid-derived suppressor cells

Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells

Combination therapy strategies for improving PD-1 blockade efficacy: a new era in cancer immunotherapy

STAT3 Induces Immunosuppression by Upregulating PD-1/PD-L1 in HNSCC

JAK-STATmediated chronic inflammation impairs cytotoxic T lymphocyte activation to decrease anti-PD-1 immunotherapy efficacy in pancreatic cancer

PD-L1 expression on tolerogenic APCs is controlled by STAT-3

The EGFR pathway is involved in the regulation of PD-L1 expression via the IL-6/JAK/STAT3 signaling pathway in EGFR-mutated non-small cell lung cancer

Cancer-associated fibroblasts induce PDL1+ neutrophils through the IL6-STAT3 pathway that foster immune suppression in hepatocellular carcinoma

Glioblastoma-Derived IL6 Induces Immunosuppressive Peripheral Myeloid Cell PD-L1 and Promotes Tumor Growth

Tumor stroma-derived factors skew monocyte to dendritic cell differentiation toward a suppressive CD14(+) PD-L1(+) phenotype in prostate cancer

IL-6: a cytokine at the crossroads of autoimmunity

Approaches and advances in the genetic causes of autoimmune disease and their implications

Environmental control of autoimmune inflammation in the central nervous system

Back to central tolerance

A four-step model for the IL-6 amplifier, a regulator of chronic inflammations in tissue-specific MHC class II-associated autoimmune diseases

Cancer is a preventable disease that requires major lifestyle changes

Serum interleukin 6 levels in rheumatoid arthritis: correlations with clinical and laboratory indices of disease activity

Interleukin-6 is a prognostic factor in multiple myeloma

Human helper T cell factor(s) (ThF). I. Partial purification and characterization

Human helper T cell factor(s) (ThF). II. Induction of IgG production in B lymphoblastoid cell lines and identification of T cell-replacing factor-(TRF) like factor(s)

Serum immunoglobulin levels in patients with active pulmonary tuberculosis and patients with Klebsiella infection

Induction of plasma-cell neoplasms in strain BALB/c mice with mineral oil and mineral oil adjuvants

Induction of plasma cell tumours in BALB-c mice with 2,6,10,14-tetramethylpentadecane (pristane)

Genetics of susceptibility to pristane-induced plasmacytomas in BALB/cAn: reduced susceptibility in BALB/cJ with a brief description of pristane-induced arthritis

A macrophage-derived factor required by plasmacytomas for survival and proliferation in vitro

Induction of lupus-associated autoantibodies in BALB/c mice by intraperitoneal injection of pristane

Generation of plasmacytomas with the chromosomal translocation t(12;15) in interleukin 6 transgenic mice

Interleukin-6 and the acute phase response

Fever produced by intrahypothalamic injection of interleukin-1 and interleukin-6

Interleukin 6 is required for the development of collagen-induced arthritis

Interleukin 6 plays a key role in the development of antigen-induced arthritis

IL-6-deficient mice resist myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis

IL-6-deficient mice are resistant to experimental autoimmune encephalomyelitis: roles of IL-6 in the activation and differentiation of autoreactive T cells

Disparate T cell requirements of two subsets of lupusspecific autoantibodies in pristane-treated mice

Defective development of pristane-oil-induced plasmacytomas in interleukin-6-deficient BALB/c mice

The point mutation of tyrosine 759 of the IL-6 family cytokine receptor gp130 synergizes with HTLV-1 pX in promoting rheumatoid arthritis-like arthritis

Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice

Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas

Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression

Therapeutic targeting of IL-6 trans signaling counteracts STAT3 control of experimental inflammatory arthritis

Correlation of serum interleukin-6 levels with joint involvement and thrombocytosis in systemic juvenile rheumatoid arthritis

Clinical relevance of serum interleukin-6 in Crohn's disease: single point measurements, therapy monitoring, and prediction of clinical relapse

Cytokine patterns in cancer patients: A review of the correlation between interleukin 6 and prognosis

Interleukin-6-174G > C (rs1800795) polymorphism distribution and its association with rheumatoid arthritis: A case-control study and meta-analysis

Association of interleukin-6 gene polymorphism with coronary artery disease: an updated systematic review and cumulative meta-analysis

The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis

Association between interleukin-6 gene polymorphisms and rheumatoid arthritis in Chinese Han population: a case-control study and a meta-analysis

Signal transducer of inflammation gp130 modulates atherosclerosis in mice and man

Genetics of rheumatoid arthritis contributes to biology and drug discovery

Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci

A functional IL-6 receptor (IL6R) variant is a risk factor for persistent atopic dermatitis

Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours

Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma

Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma

The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis

A non-conservative polymorphism in the IL-6 signal transducer (IL6ST)/gp130 is associated with myocardial infarction in a hypertensive population

Persistently activated Stat3 maintains constitutive NF-kappaB activity in tumors

Essential role of cooperative NF-kappaB and Stat3 recruitment to ICAM-1 intronic consensus elements in the regulation of radiation-induced invasion and migration in glioma

NF-kappaB, inflammation, immunity and cancer: coming of age

IL-6 is produced by osteoblasts and induces bone resorption

Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion

Cytokines alter IgA1 Oglycosylation by dysregulating C1GalT1 and ST6GalNAc-II enzymes

Human interleukin 6 is a direct promoter of maturation of megakaryocytes in vitro

Interleukin-6 is a potent thrombopoietic factor in vivo in mice

Interleukin-6 and aging: blood levels and mononuclear cell production increase with advancing age and in vitro production is modifiable by dietary restriction

Gateway reflex: neural activation-mediated immune cell gateways in the central nervous system

Molecular and Functional Neuroscience in Immunity

Neuroendocrine modulation of signal transducer and activator of transcription-3 in ovarian cancer

A new regulation of IL-6 production in adult cardiomyocytes by beta-adrenergic and IL-1 beta receptors and induction of cellular hypertrophy by IL-6 trans-signalling

Origin and Function of Stress-Induced IL-6 in Murine Models

Senescence-associated inflammatory responses: aging and cancer perspectives

Inflammaging and 'Garb-aging

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan

Aging immunity may exacerbate COVID-19

PIM-1 modulates cellular senescence and links IL-6 signaling to heterochromatin formation

Altered regulation of IL-6 production with normal aging. Possible linkage to the age-associated decline in dehydroepiandrosterone and its sulfated derivative

Interleukin-6 and its receptor in cancer: implications for translational therapeutics

Acceleration of beta Cell Aging Determines Diabetes and Senolysis Improves Disease Outcomes

Genetics, pathogenesis and clinical interventions in type 1 diabetes

Immune mechanisms in type 1 diabetes

An IL-6 link between obesity and cancer

Signaling: The Missing Link between Obesity and Inflammation-Driven Liver and Colorectal Cancers. Cancers (Basel)

Hypoxia in adipose tissue: a basis for the dysregulation of tissue function in obesity?

TLR4 links innate immunity and fatty acid-induced insulin resistance

Tlr-4 deficiency selectively protects against obesity induced by diets high in saturated fat

Fatty acidinduced induction of Toll-like receptor-4/nuclear factor-kappaB pathway in adipocytes links nutritional signalling with innate immunity

STAT3-induced S1PR1 expression is crucial for persistent STAT3 activation in tumors

Sphingosine-1-phosphate links persistent STAT3 activation, chronic intestinal inflammation, and development of colitis-associated cancer

Constitutively activated Jak-STAT pathway in T cells transformed with HTLV-I

Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein

Distinct tumorigenic potential of abl and raf in B cell neoplasia: abl activates the IL-6 signaling pathway

A single amino acid substitution in the v-Eyk intracellular domain results in activation of Stat3 and enhances cellular transformation

Requirement of the NF-kappaB subunit p65/RelA for K-Ras-induced lung tumorigenesis

KrasG12D-induced IKK2/beta/NF-kappaB activation by IL-1alpha and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma

Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer

Mesothelin confers pancreatic cancer cell resistance to TNF-alpha-induced apoptosis through Akt/PI3K/NF-kappaB activation and IL-6/Mcl-1 overexpression

Mesothelin overexpression promotes autocrine IL-6/sIL-6R trans-signaling to stimulate pancreatic cancer cell proliferation

HER2 overexpression elicits a proinflammatory IL-6 autocrine signaling loop that is critical for tumorigenesis

Loss of p53 in enterocytes generates an inflammatory microenvironment enabling invasion and lymph node metastasis of carcinogen

Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer

The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors

Revisiting STAT3 signalling in cancer: new and unexpected biological functions

A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses

Helicobacter pylori cytotoxin-associated gene A activates the signal transducer and activator of transcription 3 pathway in vitro and in vivo

Activation of STAT3 by the hepatitis C virus core protein leads to cellular transformation

Deactivation of Akt and STAT3 signaling promotes apoptosis, inhibits proliferation, and enhances the sensitivity of hepatocellular carcinoma cells to an anticancer agent

Hepatitis B virus promotes cancer cell migration by downregulating miR-340-5p expression to induce STAT3 overexpression

Epstein-Barr virus-derived EBNA2 regulates STAT3 activation

PTEN is a negative regulator of STAT3 activation in human papillomavirus-infected cells

Acute Respiratory Distress Syndrome

SARS and MERS: recent insights into emerging coronaviruses

Cytokine Storms: Understanding COVID-19

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)?

Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19

An inflammatory cytokine signature predicts COVID-19 severity and survival

Nucleocapsid protein of SARS-CoV activates interleukin-6 expression through cellular transcription factor NF-kappaB

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

SARS coronavirus-induced lung injury

Angiotensinconverting enzyme 2 protects from severe acute lung failure

Understanding Angiotensin II Type 1 Receptor Signaling in Vascular Pathophysiology

Vascular inflammation and the renin-angiotensin system

Pleiotropic AT1 receptor signaling pathways mediating physiological and pathogenic actions of angiotensin II

Cytokine release syndrome in severe COVID-19

The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease

Chimeric antigen receptor T-cell therapy -assessment and management of toxicities

Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells

CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade

Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury

Tocilizumab attenuates acute lung and kidney injuries and improves survival in a rat model of sepsis via down-regulation of NF-kappaB/JNK: a possible role of P-glycoprotein

Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome

SARS-CoV-2 infections and COVID-19 mortalities strongly correlate with ACE1 I/D genotype

An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels

Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension

Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19

Renin-angiotensin system inhibitors and the severity of coronavirus disease 2019 in Kanagawa

Angiotensinconverting enzyme inhibitors and angiotensin-receptor blockers and the risk of COVID-19 infection or severe disease: Systematic review and meta-analysis

Chimeric antigen receptor T cells for sustained remissions in leukemia

Effective treatment of severe COVID-19 patients with tocilizumab

Tocilizumab treatment in COVID-19: A single center experience

Tocilizumab for the treatment of severe coronavirus disease

Comparative Survival Analysis of Immunomodulatory Therapy for Coronavirus Disease

Baricitinib restrains the immune dysregulation in patients with severe COVID-19

Dexamethasone in Hospitalized Patients with Covid-19 -Preliminary Report

Letter to the Editor: Obesity as a risk factor for greater severity of COVID-19 in patients with metabolic associated fatty liver disease

Diabetes is a risk factor for the progression and prognosis of COVID-19

COVID-19 and Cardiovascular Disease

Targeting Interleukin-6 Signaling in Clinic

High-performance medicine: the convergence of human and artificial intelligence

Physics of life: The dawn of quantum biology

The future of quantum biology

Acknowledgements I appreciate Dr. P. Karagiannis (CiRA, Kyoto University, Kyoto, Japan) for critical reading the manuscript. The author declares he has no financial or non-financial competing interests.