key: cord-0005978-hrobttf9 authors: Javeed, A.; Zhao, Y.; Zhao, Y. title: Macrophage-migration inhibitory factor: role in inflammatory diseases and graft rejection date: 2008-02-21 journal: Inflamm Res DOI: 10.1007/s00011-007-7110-6 sha: 767d08c1aaaff6ee2e5e58789db91cc5a8e568ff doc_id: 5978 cord_uid: hrobttf9 Macrophage migration inhibitory factor (MIF) functions as a pleiotropic protein, participating in inflammatory and immune responses. MIF was originally discovered as a lymphokine involved in delayed hypersensitivity and various macrophage functions, including production of proinflammatory cytokines, glucocorticoid-induced immunomodulator, and natural killer cell inhibitory factor (NKIF), regulation of toll-like receptor expression, adherence and phagocytosis of macrophages, as well as induction of metalloproteinase. Therefore MIF is considered as a potential target protein in many pathophysiological states. In this review, considering the protein structure and the acting mechanisms of MIF, we mainly discuss the important role of MIF in pathogenesis of inflammatory diseases and graft rejection. Macrophage migration inhibitory factor (MIF) was originally found to inhibit the random migration of macrophages as a T-lymphocyte-derived activity [1] and was associated with delayed-type hypersensitivity reactions, infl ammatory arthritis [2] , glomerulonephritis [3] , allograft rejection [4] and wound healing [5] . MIF can signifi cantly modify the activation, adherence, phagocytosis and nitric oxide (NO) production of macrophages [6, 7] . Neutralization of MIF in animal models of infl ammatory diseases such as arthritis, glomerulonephritis and acute lung injury has pronounced therapeutic effects. However, molecular characterization of the protein responsible for this activity and its role in the immune response has remained elusive. In addition to its role in hypersensitivity reactions, recent studies with MIF -/mice confi rmed the paramount importance of this protein in sepsis Correspondence to: Y. Zhao the PI3K/Akt pathway and this effect is critical for tumor cell survival [19] . Furthermore, an intracellular receptor protein for MIF, i. e. co-activator c-jun activation domain binding protein-1(JAB1), has been identifi ed [19] . Glucocorticoids have been administered clinically to treat infl ammatory and autoimmune diseases for over fi ve decades. They exert positive and negative effects on immune responses, e. g. glucocorticoids are involved in gene modulation during priming of the innate response, while they suppress cellular (Th1) and promote humoral (Th2) immunity [20] . It is considered that glucocorticoids inhibit cytokine expression but induce MIF expression by monocytes, macrophages and Tlymphocytes. MIF was described as the fi rst pro-infl ammatory cytokine to be produced upon glucocorticoid stimulation [21] . Due to the pro-infl ammatory effect of MIF and anti-infl ammatory effect of glucocorticoids on immune cell activation, MIF acts as counterregulatory mediator that counteracts the immunosuppressive effects of glucocorticoids [22] . In particular MIF counteracts glucocorticoid-induced inhibition of infl ammatory cytokine secretion in T cells [23] . Current data indicate that MIF may play an important role in the infl ammatory cascade. The association of glucocorticoid counter-regulating activity of MIF with its redox rather than tautomerase activity was suggested by the fi nding of structure-function correlations [24] . The ERK MAP kinase activation [25] causes phosphorylation and prolongs activation of cytoplasmic phospholipase A 2 (cPLA 2 ), which was later confi rmed [26] . This effect may lead to glucocorticoid receptor (GR) antagonism, with no alteration in GR expression or affi nity [27] . cPLA 2 and its products, such as arachidonic acid, play a critical role in infl ammatory reactions and are involved in activation of c-Jun N-terminal (JNK)/stress activated protein kinase (SAPK) pathways [28] . The blocking of JNK/SAPK activation induces glucocorticoid inhibition of tumor necrosis factor-a (TNF-a) translation [29] . MIF ability to activate cPLA 2 may lead to counter-regulation of the immunosuppressive effect of glucocorticoids. The effects of MIF on MAP kinase phosphatase-1 and p38 MAP kinase may regulate the sensitivity of cells to glucocorticoid [16] . MIF is a ubiquitous protein performing an important role in the pathogenesis of various infl ammatory disease conditions in different organs such as kidney, heart, lung, liver, skin and so on [30] . Here, we briefl y discuss the role of MIF in various autoimmune diseases. Over-expressing MIF could remarkably accelerate the progression of glomerulosclerosis and end-stage renal failure [31] . The urine MIF concentration was signifi cantly increased in proliferative forms of glomerulonephritis (GN) and correlated with the degree of renal dysfunction, histologic damage and leukocytic infi ltration. Urine MIF refl ected MIF expression in the injured kidney [32] . MIF performs a regulatory role in the pathogenesis of immunologically induced kidney disease [33] [34] [35] . Anti-MIF mAbs or defi ciency of MIF signifi cantly inhibited focal lesions and glomerular crescent formation, minimizing glomerular macrophage and T-cell infi ltration and activation [36] . This treatment inhibited IL-1, glomerular, interstitial and tubular inducible nitric oxide (NO) synthase expressions. MIF is closely related with the occurrence of rheumatoid arthritis (RA) [37] . Elevated levels of MIF were found in typical RA infl ammatory sites i. e. 5 to 10 fold higher than in normal volunteers. The MIF was released by infi ltrating T lymphocytes, macrophages and synovial cells in synovial fl uid. Anti-MIF mAb signifi cantly suppressed the infl ammatory response in experimentally induced arthritis in mouse models [2] . The typical pathological feature of RA is the connective tissue degradation by matrix metalloproteinases (MMPs). MIF is involved via up-regulation of MMP-1 and MMP-3 mRNA levels in synovial fi broblasts [38] . MMP-1 and MMP-3 are considered to be involved in the degradation of extracellular matrix components in RA. Furthermore, MIF polymorphisms are closely related with increased clinical disease severity and increased risk of joint erosions and damage in adult patients with RA [39] [40] [41] . The proliferation of human RA synoviocytes, inhibition of p53 expression and apoptosis in these cells by MIF demonstrate the role of MIF in human RA [42, 43] . Recently, the suppression of collageninduced arthritis (CIA) in MIF -/mice [44] confi rms the role of MIF in RA. These data suggest that MIF inhibition could have signifi cant importance as a therapeutic target in RA. In all stages of human atherosclerosis, an elevated MIF expression and functional co-localization with JAB1 were observed [43, 45] . MIF is up-regulated in endothelial cells (EC), smooth muscle cells (SMC) and macrophages during progression of atherosclerosis in humans and hypercholesterolemic rabbits. Activated CD68 + macrophages adherent onto MIF + vascular endothelial cells increased MIF expression [46] , which indicated a key role of MIF in atherosclerosis. An increased MIF-mediated monocyte arrest in the endothelium suggests a crucial role of MIF in leukocyte recruitment in atherogenesis [47] . The vascular infl ammation, cellular proliferation and neointimal thickening were reduced by neutralizing MIF bioactivity after experimental angioplasty in atherosclerosis-susceptible mice [48] . The genetic deletion of MIF in LDLR -/mice reduced lipid deposition and intimal thickening in the aorta. Neutralizing anti-MIF mAb or peripheral MIF depletion in ApoE -/mice signifi cantly reduced the infl ammatory response associated with atherosclerosis development, including reductions in concentrations of circulating and lesional infl ammatory cytokines, lesional adhesion molecules and MMPs, and expression of infl ammatory transcription factors. These recent studies demonstrated that MIF expression was closely correlated with atherosclerotic disease severity [43] . A signifi cant quantity of MIF was found in the alveolar air spaces, which indicates the potential role of MIF in acute respiratory distress syndrome (ARDS) [49] . Increased MIF expression was confi rmed in ARDS patients [50] . MIF plays a role in ARDS via up regulation of the neutrophil chemoattractant macrophage infl ammatory protein-2 (MIP-2). An elevated level of MIF expression was shown in both lung tissues and bronchoalveolar lavage (BAL) fl uids in the development of acute injury [51] . Anti-MIF antibody signifi cantly reduced the accumulation of infl ammatory cells and also reduced TNF-a expression in air spaces. Furthermore, human eosinophils are potent sources of MIF. Eosinophils are the key cells in the pathogenesis of allergic infl ammatory diseases such as atopic dermatitis, allergic rhinitis and bronchial asthma [52] . MIF is involved in the immunopathogenesis of asthma possibly via the promotion of Th2 responses. MIF inhibition in asthma may be therapeutically benefi cial and specifi c intervention may be guided by the MIF genotype of affected individuals [53] . However, recent studies showed that MIF is required for allergic infl ammation but not for Th2 differentiation [54] and without affecting immune response [55] . These data suggest that MIF may contribute to the pulmonary infl ammatory response in asthma and other allergic infl ammatory conditions. Increased level of MIF was noticed in the serum and liver of patients with hepatitis, alcoholic liver disease and cirrhosis [56, 57] . Neutralizing anti-MIF mAb signifi cantly inhibited the severity of hepatitis by reducing the level of transaminase in sera and inhibited TNF-a production. In addition, acute hepatitis in mice was prevented by anti-sense MIF cDNA [58] , which reduced the necrotic area in liver. Anti-mouse MIF antibody treatment reduced liver injury and infl ammatory cell infi ltration in the liver after injection of antigen-specifi c cytotoxic T lymphocytes into hepatitis B virus transgenic mice [59] . These fi ndings suggest the therapeutic potential of MIF in hepatitis. An experimental model of pancreatitis induced by taurocholic acid showed the involvement of MIF in the pathogenesis of pancreatitis [60] . It was observed that MIF expression was signifi cantly increased systemically and locally in patients with pancreatitis [61, 62] . Anti-MIF antibody treatment signifi cantly decreased the severity of pancreatitis [60] . In mice with acute gastric ulcer, macrophages were the major source of up-regulated MIF. Anti-MIF antibody significantly inhibited the up-regulation of TNF-a and inducible NO synthase and intercellular adhesion molecule-1 [63] . Helicobactor pylori infection induced signifi cantly high levels of MIF protein and mRNA expressions in epithelial cells, T cells and macrophages, which suggest a role of MIF in stomach disease [64, 65] . Crohn's disease (CD) and ulcerative colitis (UC) showed enhance a MIF protein in the serum of these patients [66, 67] . In experimental colitis, MIF expression was increased during colitis and the severity of colitis was reduced by anti-MIF antibody [68] , which suppressed T-helper 1-type cytokines and matrix metalloproteinase (MMP). It has been reported that MMP is overexpressed in infl ammatory bowel disease (IBD) and in experimental colitis [69] . Moreover, MIF-defi cient mice showed mild infl ammation compared with wild-type mice [70] . Increasing expression of MIF was observed in acute neonatal necrotizing enterocolitis [71] . Colitis in acute graft-versus-host disease (GVHD) was correlated with local upregulation of MIF [72] . In addition, MIF may also be involved in intestinal tumorigenesis [73] . H. pylori induced gastritis, intestinal metaplasia and gastric cancer had progressively increased epithelial and serum MIF expression, suggesting that MIF is involved in gastric carcinogenesis and may be a valuable biomarker for the early detection of gastric cancer [74] .Various colon cancers in vivo and in vitro exhibited increased MIF level [75] . MIF expression was associated with enhanced cell proliferation. Anti-MIF antibody markedly inhibited tumor growth [75] . These studies suggest that MIF may be a possible indicator of prognosis in colorectal cancer. A potent innate immune response is initiated by ischemiareperfusion (I/R) injury during the process of harvesting, transporting, and implanting a transplanted organ [76] . Liver I/R and surgical injury causes induction of transcripts for the cytokines including IL-10, IL-1a,IL-1b, IL-1Ra, IL-18, IL-6, INF-b, MIF, IL-6, INF-g, TGF-b1, RANTES, major intrinsic protein MIP-1b, MIP-1a, MIP-2, IFN--inducible protein (IP)-10, MCP-1 and TCA-3 [77, 78] . Allografts can induce macrophage accumulation and the overall macrophage accumulation promotes a rejecting immune response. The infi ltration of recipient-derived macrophages was observed in the graft within 24 h after surgery [79] . MIF participates in the recruitment of circulating monocytes into rejecting organs and, as a pro-infl ammatory molecule, is involved in cell-mediated immunity and delayedtype hypersensitivity [3, 80] . MIF promotes the production of pro-infl ammatory cytokines as activated macrophages can secret IL-1, IL-2, IL-18, TNF-a and IFN-g [81] . These proinfl ammatory cytokines are associated with graft rejection [82, 83] . The pivotal role of MIF in infl ammation and graft rejection is briefl y summarized in Figure 1 . MIF may be an important mediator in the allo-immune reaction during renal transplantation. TNF-a involves upregulation of local MIF expression by both infi ltrating macrophages and resident kidney cells in rat crescentic glomerulonephritis. Systemic MIF production is also regulated by TNF-a. Thus, both TNF-a and MIF may participate in the pathogenesis of immunological by induced renal disease [33] . Glomerular macrophage accumulation was reported in severe allograft rejection with worse prognosis which highlights the importance of MIF in renal transplantation [84] . As local MIF production is increased in acute renal allograft rejection, urine MIF may be used as a diagnostic tool in human renal allograft rejection [32, 85] . However, studies using MIF -/mouse models did not support the important role of MIF in kidney or heart allo-graft rejection [86] . Though MIF blockade signifi cantly reduced the delayed-type hypersensitivity response; neither local nor systemic MIF are required for the rejection of fully mismatched skin and renal allo-grafts [87] . It is worth noting that MIF participates in skin graft destruction after indirect recognition through an inhibition of macrophage migration and/or function [4] . Thus whether MIF plays different roles in direct and indirect antigen recognition in transplants needs to be addressed. Pancreas transplantation offers a cure for diabetes mellitus. Some immune modulating proteins, monocyte chemoattractant protein-1(MCP-1), transforming growth factor-β (TGF-β) [88] and MIF [89] are expressed in islets of Langherhans. These proteins could be involved in the development of autoimmunity in type-1 diabetes and infl uence intraportal islet transplantation outcome [90] [91] [92] . Isolated islets expressed several infl ammatory mediators, particularly at an early stage after isolation, suggesting that a few days culture could be benefi cial for outcome of islet transplantation [92] . In addition, the important role of MIF in the development of acute GVHD in a mouse model of allogeneic stem cell transplantation has been reported [93] . MIF was thus found to be one of the major cytokines involved in the rejection of the allogeneic tracheal; treatment with MIF siRNA inhibits the destruction of tracheal allografts and formation of obstructive bronchiolitis in the early phase [94] . A number of questions about the pathophysiological significance of MIF remain to be answered. It is currently known that MIF is a pro-infl ammatory cytokine that plays a critical role in infl ammation and cellular immunity. MIF is an important mediator in the pathogenesis of infl ammatory disorders such as endotoxemia/sepsis, arthritis, glomerulonephritis, pancreatitis, infl ammatory bowel disease, tumorigenesis as well as several other pathophysiologic infl ammatory and immune conditions. MIF may also be closely involved in allograft rejection and dysfunction. Anti-MIF antibodies have proved to be a potent tool for effective treatment of human infl ammatory diseases. MIF inhibitors may have potential therapeutic applications in patients with infl ammatory diseases or allo-grafts in the clinic. 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