key: cord-0844315-cvk2qriy authors: Joshi, Meghnad G.; JeevitaaKshersagar; Desai, Shashikant R.; Sharma, Shimpa title: Antiviral properties of placental growth factors: A novel therapeutic approach for COVID-19 treatment date: 2020-08-06 journal: Placenta DOI: 10.1016/j.placenta.2020.07.033 sha: fa9d0e6c65407e8dff28c606d240ac04f9d690a3 doc_id: 844315 cord_uid: cvk2qriy The current challenge of the COVID-19 pandemic is complicated by the limited therapeutic options against the virus, with many being anecdotal or still undergoing confirmatory trials, underlining the urgent need for novel strategies targeting the virus. The pulmotropic virus causes loss of oxygenation in severe cases with acute respiratory distress syndrome (ARDS) and need for mechanical ventilation. This work seeks to introduce placental extract-derived biologically active components as a therapeutic option and highlights their mechanism of action relevant to COVID-19 virus. Human placenta has been used in clinical practice for over a century and there is substantial experience in clinical applications of placental extract for different indications. Aqueous extract of human placentacontains growth factors, cytokines/chemokines, natural metabolic and other compounds, anti-oxidants, amino acids, vitamins, trace elements and biomolecules, which individually or in combination show accelerated cellular metabolism, immunomodulatory and anti-inflammatory effects, cellular proliferation and stimulation of tissue regeneration processes. Placental extract treatment is proposed as a suitable therapeutic approach consideringthe above properties which could protect against initial viral entry and acute inflammation of alveolar epithelial cells, reconstitute pulmonary microenvironment and regenerate the lung. We reviewed useful therapeutic information of placental biomolecules in relation to COVID-19 treatment. We propose the new approach of using placental growth factors, chemokines and cytokine which will execute antiviral activity in coordination with innate and humoral immunity and improve patient's immunological responses to COVID-19. Executing a clinical trial using placental extract as preventive, protective and/or therapeutic approach for COVID-19treatment could advance the development of a most promising therapeutic candidate that can join the armamentaria against the COVID-19 virus. Tyrrell and Bynoein 1965 identified a virus responsible for common cold from human embryonic tracheal organ cultures and they named it as B814 (1) . In 1967, Almeida and Tyrrell performed electron microscopy study on fluids from organ cultures infected with B814and found particles sized (80-150 nm) that resembled the infectious bronchitis virus of chickens (2) . In 1975, Tyrrell suggesting sustained human-to-human transmission (6) . To date the infection was believed to be transmitted through airborne respiratory droplets and physical contact (7) .The recent detection of corona virus in the faeces of confirmed patients in Wuhan, Shenzhen and the first case in the United States, indicates that the virus can replicate in the digestive tract and exist, suggesting a potential forfaeco-oral transmission (8) . In December 2019, Wuhan, China experienced an outbreak of a novel coronavirus that killed more than thirty three hundred and infected over eighty two thousand individualstill date. This virus was reported to be a member of the β group of coronaviruses. The novel virus was named as Wuhan coronavirus or 2019 novel coronavirus (2019-nCoV) by the Chinese researchers which was subsequently renamed the CoVID-19 virus (9) . J o u r n a l P r e -p r o o f The mechanism of CoVID-19of attachment, replication and cellular changes during the infection are presented in Fig. 2 .Coronaviruses replication is facilitated by specific genes in ORF1 downstream regionsthat also encode proteins for nucleocapsid and spikes formation (10) . The virus attaches to host cell through glycoprotein spikes on the outer surface (Fig 1) .Coronavirusinfect multiple hosts due to loosely attached receptor-binding domain (RBD). SARS-CoV caused systemic spread of severe lower respiratory disease with 10% mortality. Recently, another human coronavirus-Erasmus Medical Center (hCoV-EMC)) was recognized in severe lower respiratory tract infectionpatients. Viral genome of hCoV-EMC is similar to coronaviruses found in bats. The dipeptidyl peptidase 4 (DPP4) act as a functional receptor for hCoV-EMC. Expression of DPP4 protein provides clues about the host range potential of hCoV-EMC (11) . The entry mechanism of a coronavirus depends upon cellular proteases present in human airway such as trypsin-like protease (HAT), cathepsins and transmembrane protease serine 2 (TMPRSS2) that split the spike protein and establish further penetration changes. Coronavirus require angiotensin-converting enzyme 2 (ACE2) as a key receptor for cellular penetration. Researchers have confirmed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses SARS-CoV receptor angiotensin-converting enzyme 2 (ACE2) for host cell entry (12) . The presently known pathogenesis of CoVID-19 infection is presented in (Fig. 2 :3,4, and 5) with knowledge on this still evolving. It is important to note that the human immunological system is naive for this virus increasing the vulnerability of the species. The virus has a R0 of 2.5 which with its' airborne transmission makes it a challenge to contain, even compared to influenza virus. It is also infectious when the index case is completely asymptomatic and can stay alive on fomites for few hours to days. The mechanisms of SARS-CoV and MERS-CoVpathogenesis is very similar and can give us information on the pathogenesis. Once the virus enters the cells, its antigen will be presented to the antigen presentation cells(APC), Macrophages and Dendritic cells which trigger anti-viral immunity. Antigenic peptides are presented by human leukocyte antigen (HLA) and then recognized by virus-specific cytotoxic T lymphocytes (CTLs). These cytotoxic cells start to release of large amounts of proinflammatory cytokines (IFN-α, IFN-γ, IL-1β, IL-6, IL-12, IL-18, IL-33, TNF-α, TGFβ, etc.) and chemokines (CCL2, CCL3, CCL5, CXCL8, CXCL9, CXCL10, etc.) (13) (14) (15) . The uncontrolled systemic inflammatory responses resulting in cytokine storm, which releases large amounts of pro-inflammatory cytokines. The cytokine storm triggers a violent attack by J o u r n a l P r e -p r o o f the immune system to the body, cause acute respiratory distress syndrome (ARDS) which leads to pulmonary oedema and lung failure, and have liver, heart, and kidney damages and finally lead to death in severe cases of CoVID-19.The cytokine storm launches a violent attack on the body organs, causing ARDS as well as hepatic, cardiac and renal damage leading to the mortality seen in severe cases of CoVID-19 (16) . Innate and adaptive immune systems function to tackle the daily exposure to pathogens the human body faces. Innate (non-specific, natural) immunity provides the initial and immediate response of the body based on broad pathogen specificity and is mediated by Dentritic cells, macrophages and B cells. Adaptive (learnt, specific) immunity responds to antigens/pathogens and is mediated by B cells, T-lymphocytes, Natural Killer Cells and eeffector lymphocytes. In both cases, the tissue-specific cells release small functional proteins called cytokines to attract immune system components to reach the site.Probable protective mechanism and involvement of cytokine and chemokines for COVID-19 infection is presented in Figure 5 . Cytokines play a key role in cell-to-cell communication within IL-4, IL-5 and IL-10 and function to destroy infected and injured cells. Naïve CD8+ helper cells are recruited by DCs with an important role played by the chemokine-chemokine receptor pair XCL1-XCR1 which may also form a 'feed-forward loop between the CD8 + T cells and the DCs'. Recruitment of CD8+ lymphocytes is also regulated by IL-2 and chemokines released by the CD4+ Helper T-lymphocytes. One of the downstream targets of IL-2 signalling in promotion of CD8+ recruitment is the MAPK molecular pathway (31) . It has been shown in coronavirus infections that IL-10 production may be promoted by strong T-Cell Receptors-MAPK signalling. This is significant as IL-10 is a cytokine that 'prevent immunopathology during viral infection without affecting the kinetics of viral clearance (32) . J o u r n a l P r e -p r o o f Symptoms of CoVID-19 infection are mostly non-specific and the disease presentation can range from asymptomatic to severe pneumonia and death (34) .Symptoms of COVID-19 may appear 2 to 14 days after exposure and can includefever, cough, fatigue, sputum production, headache, haemoptysis, diarrhoea and dyspnoea (16, 35) .Difficulty in breathing is associated with progressive hypoxemia not fully corrected by mechanical ventilation (36) . Like all viral pneumonias, the risk of secondary bacterial infections can be a complication in patients worsening prognosis. Elderly patients and patients with co-morbidities, immunocompromised or immunosuppressed have been seen to have worse prognosis compared to others.In elderly patients, COVID-19 infection results in lower respiratory tract followed to fatal pneumonia. Vulnerable groups especially the elderly are more susceptible to developing lower respiratory tract infections and fatal pneumonia (37, 38) .In a study from China, patients with severe disease were older (than non-severe patients) by a median of 7 years and those needing ICU information about whether a person may have been exposed". In a letter to health care workers, the FDA recommends that the test could be used to identify those exposed to the infection or recovered from it to as they could serve as potential donors for manufacture of convalescent plasma. Current The placenta is a large lobular temporary organ that develops upon implantation of the blastocyst into the endometrium. This vascular organ is attached to the uterine wall and forms a conduit for maternal blood to provide oxygen, glucose and biologically active substances for the growth and development of the foetus. The placenta contains a wide range of biologically active components such as growth factors, Cytokine/chemokine, natural Metabolic and other compounds, anti-oxidants, Amino acids, Vitamins and Trace Elements (Fig. 3) .Importantly, the placenta is capable of producing all substances found in any organ of the body (46) . The placenta is considered to be bio-waste after delivery and thistreasure of bioactive compounds many a time goes waste.Use of human placenta has been a part of folk remedy in Oriental countries and there is substantial experience of over a century in the application of the placental extract (PE)for experimental and clinical practice.In Japan, the hydrolysate of human placenta, which contains therapeutic compounds, has long been refined as human placental extract (HPE). In India, several studies have been made on the application of PE as wound healing material (47) . Aqueous extract of human placenta showsaccelerated cellular metabolism, absorption of exudates, effects debridement, antibacterial activityand stimulates tissue regeneration processes (48 The Placenta, is considered an ideal example of allograft, and it plays an important role of immunomodulation to maintain an environment conducive to foetal development. Th2-type cytokines (72) . The placenta acts as a immunological barrier between the mother and fetus and protects the developing fetus from the transmission of viruses.The aqueous extract of human placenta is a depot of growth factors, chemokines and cytokine which execute antiviral activity in coordination with innate and humoral immunity. Interferons (IFNs) are a large family of cytokines defined by their ability to confer resistance to viral infections and providing rapid and broad protection against a wide variety of invading pathogens. Placental trophoblastderived interferons (INF) and TNF-, have been shown to impair virus replication and activity (73, 74) . There is growing evidence that IFNs are constitutively released from human trophoblasts and play essential roles in protection against viral infection (75, 76) .Production of type I IFNs control infection systemically, and type III IFNs Table 2 . Hepatocyte Growth Factor (HGF) *Essential for organ development and Self repair *Prohibits apoptotic signals *Inhibits neutrophil infiltration *Angiogenic factor and anti-thrombosis *prohibit viral replication 2. Nerve Growth Factor (NGF) *Promotes the pathological neovascularization process. *act as an indirect activator of endothelial cell growth by stimulating the release of other vascular growth factors. *NGF stimulates the proliferation of B and T lymphocytes. *nervous and immune systems collaborate in the control of homeostasis and host defence. Epidermal Growth Factor (EGF) *Airway epithelial surface : mucin production and secretion. *Neutrophil recruitment (via interleukin-8 production) *Important role in airway epithelial repair. HGF is anmitogenic acidic protein expressed strongly in the villous syncytium, extravillous trophoblast, and amnionic epithelium, and, to a lesser degree in endothelial cells and villous mesenchyme (82) . HGFcan function as anti-apoptotic and anti-inflammatory which will have protective effects on epithelial and non-epithelial organs. HGF also plays important role inhematopoiesis that promotes the proliferation and colony formation of hematopoietic progenitors (83) . During viral infections, neutrophils, eosinophils and macrophages accelerate local or systemic inflammation resulting in tissue injury. Upon inflammatory stress, mesenchymal cells synthesize HGF that inhibitsneutrophil infiltration via the downregulation of adhesion molecules (such as ICAM-1/E-selectin) on the endothelial cell surface (84) . It has been hypothesized that reduced HGF production in elderly patients can be corrected using the placental HGF, an intervention that would be of great use in management of aspiration pneumonia, a common respiratory ailment in this age group due to impairments of swallowing and of the cough reflex(85). Shigemura, N et al administeredHGF cDNA to emphysematous rats and reported extensive pulmonary vascularization and increased proliferation of alveolar epithelial cells, which, in turn, improved exercise tolerance and gas exchange (86) .ThusHGFhas the potential to improve acute and chronic inflammatory disorders via its regenerative, anti-apoptotic, and anti-fibrotic effects. NGFis a neurotrophic peptide biomolecule that supports the growth, survival and (91) . NGFactivates interleukin-2 receptors on human peripheral blood mononuclear cellsandpromotes the growth and proliferation of human hematopietic cell (92) . NGFis also involved in chemotaxis, viability and functional properties of human polymorphonuclear neutrophils and differentiation of thymic stromal non-lymphoid cells (93). NGF can induce the shape of platelets and act as an autocrine survival factor for memory B cell (94, 95) . It is been found that NGF stimulate connective tissue mast cells and daily injections of NGF in neonatal rats resulted in robust connective tissue mast cell hyperplasia in several peripheral tissues (96, 97) . Thus, NGF carry different biological functions within and outside the nervous system. NGFinfluenced sympathetic, parasympathetic and sensory nervous system regulates immunity by antigen processing and presentation, Th1/Th2 balance, immunoglobulin production and antigen-specific responses. Importantly, NGF facilitate the collaboration between nervous and immune systems and maintainshomeostasis and host defence. This was the first ligand of the EGF Receptor which is one of the superfamily of transmembrane receptors with intrinsic Receptor Tyrosine Kinase (RTK) activity. The EGF Receptors are one of 58 RTKs through which cells receive information from the external milieu and integrate them with intracellular responses.Epidermal growth factor (EGF) receptor (EGFR), also known as ErbB1/HER1, is the prototype of the EGFR family that also includes ErbB2/HER2/Neu, ErbB3/HER3, and ErbB4/HER (98, 99) . EGF is afunctionally versatile polypeptide that plays an important role in regulating cell growth, survival, migration, apoptosis, proliferation, and differentiation. It leads to autophosphorylation of receptor tyrosine kinase (RTK) and subsequent activation of Ras/mitogen-activated protein kinases (Ras/MAPK), phosphatidylinositol 3-kinase/AKT (PI3K/AKT), phospholipase Cγ/protein kinase C (PLC-γ/PKC), and STATS signal pathways, to promote intestinal development, regulate tight junction protein expression, reduce cell autophagy, inhibit apoptosis induced by oxidative stress, and reduce the colonization of the intestinal epithelium by entero-pathogens(100).It has been linked to various cancers like small cell lung cancer, glioblastoma, head and neck cancer, breast cancer, pancreatic cancer, metastatic colorectal carcinoma through the EGFR upregulation that is commonly seen in them (99) . EGF is implicated in the morphogenesis of teeth, brain, reproductive tracts, skin, gastrointestinal tracts, in cardiovascular differentiation and function, epithelial regeneration, and corneal J o u r n a l P r e -p r o o f epithelia (101) . With respect to airways, deposition of pathogens or noxious particles on the epithelium generates an innate immune response through the EGF receptor. The EGR receptor signalling pathway produces various responses like mucin production and secretion, neutrophil recruitment (vis IL-8 production and epithelial wound healing in the lung tissue (102) . These responses through EGFR signalling also respond to mechanical stress of the respiratory epithelium. Sequential actions following EGFR signalling in mechanically stressed epithelium involves endogenous nucleotides, G-protein and non-G-Protein coupled receptors leading to IL-8 production and macrophage-release of TGF-α(103,104). . Air way epithelium is an important barrier against invading microorganisms, and epithelial innate immune mechanisms through EGFR signalling provide important pathways for repairing wounded epitheliumviamechanical stimulation. The mechanical stress, endogenous nucleotides, such as ATP and UTP, are released into the extracellular space from mechanically stressed epithelium, stimulating epithelial cell proliferation (103) . These nucleotides bind to specific G-protein-coupled receptors (GPCR) and to non-GPCRs and stimulate IL-8 production in airway epithelial cells (104) . Activated EGFR signalling activate macrophage to produce TGF and contribute in the epithelial repair process (105) . The airway epithelium is the first site of contact with inhaled viral particles. Inhaled viral particles depositing on the airway epithelial surface activate EGFR signalling pathways. EGFR activation results in the production of mucins to assist in the clearance and IL-8 recruits neutrophils, and also stimulates epithelial repair (106) . Basic fibroblast growth factor (bFGF or FGF2) is a potent mitogen for many cell types, including airway smooth muscle cells, fibroblasts, and endothelial cells (107). FGF2 can be released from inflammatory cells including T lymphocytes, eosinophil, mast cells, macrophages, and myeloid dendritic cells (108) (109) (110) . FGF carry out multiple biological processes by signalling through FGF receptors, including tumor angiogenesis, embryonic development, differentiation, proliferation, migration, and injury repair (111) (112) (113) . IGF belongs to the insulin-like growth factor family, which includes growth hormone (GH), insulin-like growth factor II (IGF2), insulin-like growth factor 1 receptor (IGF1R), insulinlike growth factor II receptor (IGF2R), and insulin-like growth factor binding protein 1-6 (IGFBP1-6) (118) . IGF family plays an important role in the cellular growth, differentiation, and apoptosis (119, 120) . IGF1 mainly functions by binding to IGF1R, a transmembrane protein composed of two α domains that binds to IGF1and activates two β domains (121) . The β domain has tyrosine kinase activity which promote the phosphorylation of the hepatocyte growth factor (HGF), docking protein insulin receptor substrate (IRS), vascular endothelial growth factor (VEGF), and growth factor receptor binding protein 2 (Grb2) (122) . IGF plays an important role in the regulation of inflammation. IGF1binds to the receptor and activates the PI3K/AKTsignalling pathway and induces Akt activation, which further activates the downstream IL-17-mediated inflammatory pathway (123) .Asthmatic patients exhibit higher bronchial cell IGF1 mRNA expression than normal people and this was associated with fibrosis in epithelial cells (124) . IGF1is known to alleviate the inflammatory response by recruiting T regulatory cells to secrete IL-10 which is the anti-inflammatory (140) . Therapeutic application of GM-CSF increases mononuclear phagocyte-mediated innate and adaptive host defense and accelerates epithelial repair processes during severe pneumonia. There is evidence that it might be a powerful antiviral therapy in pneumonia. Data suggest that GM-CSF compartment of Placental extract application seems to be most promising strategy for COVID-19 treatment. Placental Growth Factor (PlGF) is an angiogenic protein, belonging to the Vascular Endothelial Growth Factor (VEGF) family that is expressed in placenta. VEGF induces the proliferation, sprouting, and migration of endothelial cells and it regulates endothelial cell survival, and vascular permeability (141, 142) . A recent study describes the role of PlGF in cross-talk with the immune system, where PlGF was selectively secreted by activated TH17 subset of helper T-cells and stimulated neovascularization in vitro and in vivo. The study also postulated a role for PlGF in differentiation of TH17 cells and autoimmunity (143) . The VEGF has high relevance to pulmonary integrity as it affects development and structural maintenance of the lung in addition to impacting the functions through its effect on Nitric Oxide and prostacyclins. Type II pneumocytes undergo differentiation under the influence of the VEGF stimulation. Upregulation has been also described in pulmonary pathological conditions such as acute lung injury, asthma, emphysema, chronic obstructive pulmonary disease and pulmonary hypertension. Overexpression of VEGF in murine lung was seen to induce an asthma-like phenotype with inflammation, remodelling, metaplasia, hyperplasia of mycytes and dendritic cells and augmented Th2 inflammation (144) (145) (146) . An age-dependent loss of the pro-survival effect of VEGF has been described on muscle, bone, vascular endothelialcells and progenitor cells. Mitochondrial dysfunction is a phenomenon underlying the process of aging, which has been reported to block VEGF expression and contribute to impaired angiogenesis. This phenomenon may extend to the lungs and could be a possible link between the increased mortality of elderly and severe lung infections as is seen in the COVID-19 pandemic too (147, 148) . Improving understanding of the role of VEGF has been Macrophages and T cells secrete IL-6, which is a growth factor for differentiated, antibodysecreting B cells (156, 157) . The next step towards anti-viralsignalling for B cells is to develop into effector plasma cells clone the particular viral antigen. Plasma cells found in lymphoid organs and at the sites of immune responses. Effector cells generated in the mucosal immune system converted into memory cells and these clones can be reactivated when the same viral pathogen is encountered again. Thus long-lasting immunity can be achieved for secondary immune response (158) . The SARS-2 coronavirus and the resulting pandemic has taken the entire world by storm with a rapid spread and high morbidity and mortality that has challenged health care services in many countries. Large numbers of efforts are directed to finding management solutions for the disease and a cure for the virus. Regenerative medicine is one such field that has the potential to provide required answers. Clinical applications of placental extracts have been shown to be beneficial and there is now an acute need for researchers in the field to respond in a manner that satisfies the scientific temperament of this evidence-based era. This review aims to underline the immense possibilities available in this field and highlight some of the available scientific data that support further inquiry. Two predominant areas that can be targeted using placental extract are 1) Generating an early, protective immune response against SARS CoV-2 and 2) Moderating an immune overreaction such as cytokine storm that is the cause of complications and even death. It bears repetition that the placenta is an armoury with balance of inflammatory, anti-inflammatory, and immunomodulatory bioactive molecules that are potential weapons in the fight against novel, emerging infections. 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Macrophages Exhibit Distinctive Early Immune Response to Lymphocytic Choriomeningitis Virus Infection Local GM-CSF − Dependent Differentiation and Activation of Pulmonary Dendritic Cells and Macrophages Protect against Progressive Cryptococcal Lung Infection in Mice A Randomized Phase II Trial of Granulocyte-Macrophage Colony-Stimulating Factor Therapy in Severe Sepsis with Respiratory Dysfunction The discovery of the placental growth factor and its role in angiogenesis : a historical review The biology of vascular The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease VEGFR 2 but not VEGFR 3 governs integrity and remodeling of thyroid angiofollicular unit in normal state and during goitrogenesis Endothelial Cell Death and Decreased Expression of Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptor 2 in Emphysema Vascular endothelial growth factor in the lung Essential role of nitric oxide in VEGF-induced , asthma-like angiogenic , inflammatory , mucus , and physiologic responses in the lung Endothelial dysfunction and angiogenesis impairment in the ageing vasculature Inhibition of VEGF receptors causes lung cell apoptosis and emphysema Find the latest version : and emphysema Vascular Endothelial Growth Factor Gene Therapy Increases Survival , Promotes Lung Angiogenesis , and Prevents Alveolar Damage in Hyperoxia-Induced Lung Injury Evidence That Angiogenesis Participates in Alveolarization Distal Airway Stem Cells Yield Alveoli In Vitro and during Lung Regeneration following H1N1 Regulation of tissue morphogenesis by endothelial cell-derived signals Endothelial-Derived Angiocrine Signals Induce and Sustain Regenerative Lung Alveolarization Regulation of the antiinflammatory cytokines interleukin-4 and interleukin-10 during pregnancy IL-17 and Th17 Cells Type I Interferon as a Link Between Innate and Adaptive Immunity through Dendritic Cell Stimulation Type I Interferon as a Link Between Innate and Adaptive Immunity through Dendritic Cell Stimulation Interleukin-5 regulates genes involved in B-cell terminal maturation • cell survival and proliferation, inflammatory response, and anti-apoptotic factors • Control of cell growth, cell proliferation, cell differentiation • Induces immunomodulatory effects • It has antiviral, immunoregulatory, and anti-tumor properties • critical for innate and adaptive immunity against viral • Ability to inhibit viral replication directly • Regulation of immune system • Production of T, B and NK cells • Induce hyperalgesia , vasodilation and hypotension • Central regulator/mediator of immune response • Promotes/regulates the activity and growth of T cells. • Induce natural response to microbial infection • Eradicate extracellular pathogens • Regulate antibody production, • Differentiation from Th0 into Th1 and Th2 cells • Induces chemotaxis in neutrophils to migrate toward the site of infection • Potent promoter of angiogenesis. • An anti-inflammatory myokine has inhibitory effects on TNF-alpha and IL-1, and activation of IL-1ra and IL-10 • An important mediator of the immune reaction in the innate immune system response • A key role in neutrophil recruitment and degranulation. • Recruitment of inflammatory cells and induces oxidant stress mediators • Play a role in the pathogenesis of bronchiolitis by viral Infection • Important Role in immunoregulation and inflammation Downregulates the expression of Th1 cytokines, MHC class II antigens, and co-stimulatory molecules on macrophages • Enhances B cell survival, proliferation, and antibody Interleukin-1 (IL-1) Interleukin-6 (IL-6)Interleukin-8 (IL-8)Interleukin-10 (IL-10)