Macrophage migration inhibitory factor (MIF) is necessary for progression of autoimmune diabetes mellitus

Department of Immunology, Institute for Biological Research Sinisa Stankovic, Belgrade, Serbia.
Journal of Cellular Physiology (Impact Factor: 3.84). 06/2008; 215(3):665-75. DOI: 10.1002/jcp.21346
Source: PubMed


Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine of the innate immune system that plays a major role in the induction of immunoinflammatory responses. To examine the role of endogenous MIF in the pathogenesis of type 1 diabetes (TID) we evaluated the effects of administration of neutralizing anti-MIF antibodies to NOD mice with accelerated forms of diabetes induced by injection of cyclophosphamide or by transfer of diabetogenic spleen cells. Both accelerated forms of diabetes were markedly reduced by anti-MIF antibody. Furthermore, MIF-deficient (MIF(-/-)) mice were less susceptible to the induction of immunoinflammatory diabetes, insulitis and apoptosis within the endocrine pancreas by multiple low doses of streptozotocin (MLD-STZ) than genetically matched wild type (WT) mice. MIF deficiency resulted in lower proliferation and lymphocyte adhesion, as well as reduced production from the spleens and peritoneal cells of a variety of inflammatory mediators typically associated with development of the disease including IL-12, IL-23, TNF-alpha, and IL-1beta. Furthermore, MIF deletion affected the production of IL-18, TNF-alpha, IL-1beta, and iNOS in the islets of Langerhans. These data, along with the higher expression of IL-4 and TGF-beta observed in the periphery and in the pancreas of MLD-STZ-challenged MIF(-/-) mice as compared to WT controls suggest that MIF deficiency has induced an immune deviation towards protective type 2/3 response. These results suggest that MIF participates in T1D by controlling the functional activity of monocytes/macrophages and T cells and modulating their secretory capacity of pro- and anti-inflammatory molecules.

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    • "In animal models of diabetes, MIF inhibition or deletion prevents spontaneous or chemically-induced autoimmune diabetes [13] [14]. Furthermore, MIF absence protects pancreatic islets from detrimental influence of cytokines and high level of nutrients [15] [16]. "
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    ABSTRACT: Macrophage migration inhibitory factor (MIF) is a molecule with plethora of functions such as regulation of immune response, hormone-like, enzymatic and chaperone-like activity. Further, MIF is a major participant in glucose homeostasis since it is an autocrine stimulator of insulin secretion. MIF absence in male knockout mice (MIF-KO) results in development of glucose intolerance, while sensitivity to insulin is fully preserved. Since our results confirm that beta cells from MIF-KO mice express, produce and secrete insulin similarly to beta cells of their wild type (WT) counterparts C57BL/6 mice, we hypothesize that MIF-KO-derived insulin is less active. Indeed, insulin from MIF-KO islets is unable to significantly induce glucose uptake into hepatocytes and to efficiently promote insulin-triggered Akt phosphorylation determined by immunoblot. However, MIF’s tautomerase function is not crucial for insulin biosynthesis since MIF inhibitors had no impact on WT insulin activity. Importantly, MIF recognition by anti-MIF antibody (ELISA) after in vitro co-incubation with purified insulin was significantly lower suggesting that insulin covers MIF immunodominant epitope. In addition, MIF binds insulin within beta cell as confirmed by co-immunoprecipitation. WT and MIF-KO-derived insulin exhibited different cleavage patterns suggesting different protein conformations. Finally, pre-incubation of recombinant MIF with insulin promotes formation of insulin hexamers. These results imply that MIF probably enables proper insulin folding what results in insulin full activity. This newly discovered feature of the cytokine MIF could be potentially important for commercially produced insulin, for increasing its stability and/or bioavailability.
    Full-text · Article · Sep 2014 · Cytokine
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    • "Using these mice as an efficient tool, MIF was shown to be an important molecule in early syngeneic islet transplantation function, and blocking of MIF resulted in transplant success [44]. Additionally, we know that MIF participates in T1DM by controlling the functional activities of monocytes/macrophages and T cells and modulating their abilities to secrete proinflammatory molecules [45]. Furthermore, MIF has been recognized as important molecule to the development of T1DM complications such as cardiac dysfunction, which is associated with AMPK signaling [46], and diabetic foot disease [47] and is known to promote inflammatory cytokine and palmitic acid-induced pancreatic islet apoptosis [48, 49]. "
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    ABSTRACT: Autoimmunity and chronic low-grade inflammation are hallmarks of diabetes mellitus type one (T1DM) and type two (T2DM), respectively. Both processes are orchestrated by inflammatory cytokines, including the macrophage migration inhibitory factor (MIF). To date, MIF has been implicated in both types of diabetes; therefore, understanding the role of MIF could affect our understanding of the autoimmune or inflammatory responses that influence diabetic pathology. This review highlights our current knowledge about the involvement of MIF in both types of diabetes in the clinical environment and in experimental disease models.
    Full-text · Article · Jan 2014 · Journal of Diabetes Research
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    • "In contrast to other proinflammatory cytokines, MIF does not induce nuclear translocation of nuclear factor- (NF-)κB p50 or p60 proteins at concentrations that activate ERK, and inhibitors of the NF-κB pathway do not inhibit MIF-induced biological effects on FLS [64]. In addition, a recent study using an experimental diabetes model showed that MIF−/−mice are less susceptible to disease induction, and the reduced susceptibility was associated with lower levels of lymphocyte proliferation and adhesion and decreased splenic production of IL-23 [65]. Because IL-23 can enhance IL-17 production [66, 67], it may be that MIF regulates IL-17 indirectly via its effects on IL-23, which is likely involved in RA and other inflammatory disorders. "
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    ABSTRACT: Macrophage migration inhibitory factor (MIF) was originally identified in the culture medium of activated T lymphocytes as a soluble factor that inhibited the random migration of macrophages. MIF is now recognized to be a multipotent cytokine involved in the regulation of immune and inflammatory responses. Moreover, the pivotal nature of its involvement highlights the importance of MIF to the pathogenesis of various inflammatory disorders and suggests that blocking MIF may be a useful therapeutic strategy for treating these diseases. This paper discusses the function and expressional regulation of MIF in several rheumatic diseases and related conditions.
    Full-text · Article · Dec 2010
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