Macrophage migration inhibitory factor in rheumatoid arthritis.

Centre for Inflammatory Diseases, Monash University, Department of Medicine, Monash Medical Centre, Clayton, Melbourne, VIC 3168, Australia.
Frontiers in Bioscience (Impact Factor: 4.25). 02/2005; 10:12-22. DOI: 10.2741/1501
Source: PubMed

ABSTRACT Rheumatoid arthritis is characterised by the interaction of multiple mediators, among the most important of which are cytokines. In recent years, extensive data demonstrates a pivotal role for one cytokine, macrophage migration inhibitory factor (MIF), in fundamental events in innate and adaptive immunity. MIF has now been demonstrated to be involved in the pathogenesis of many diseases, but in the case of RA the evidence for a role of MIF is very strong. MIF is abundantly expressed in the serum of RA patients, and in RA synovial tissue where it correlates with disease activity. MIF induces synoviocyte expression of key proinflammatory genes including TNF, IL-1, IL-6, IL-8, cPLA2, COX2 and MMPs. MIF also regulates the function of endothelial cells and B cells. Moreover, MIF is implicated in the control of synoviocyte proliferation and apoptosis via direct effects on the expression of the tumor suppressor protein p53. In multiple rat and mouse models of RA, anti-MIF antibodies or genetic MIF deficiency are associated with significant inhibition of disease. MIF -/- mice further demonstrate increases in synovial apoptosis. That the human Mif gene is encoded by different functional alleles in subjects with inflammatory disease also provides evidence for the role of MIF in RA. The mechanism of action of MIF is becoming better understood. MIF appears to interact with cell surface CD74, with consequent activation of MAP kinases but possibly not NFkappaB intracellular signal transduction. This apparent selectivity may be implicated in the ability of MIF to antagonise the effects of glucocorticoids. As MIF expression is induced by glucocorticoids, inhibition of its antagonistic effects may permit enhanced therapeutic effect of glucocorticoids, or "steroid sparing". To date there are no clinical trials of MIF antagonism in any disease, but exploitation of antibody, soluble receptor, or small molecule approaches enabled by the unique crystal structure of MIF, may soon lead to the ability to test in the clinic the importance of this cytokine in human RA.

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    Evidence-based Complementary and Alternative Medicine 12/2014; 2014:180234. DOI:10.1155/2014/180234 · 2.18 Impact Factor
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    ABSTRACT: Macrophage Migration Inhibitory Factor (MIF) is an inflammatory cytokine that is highly produced in gastrointestinal cancers. Since chronic inflammation is a risk factor for tumorigenesis in these cancers, in this study, the role of MIF in pro-tumorigenic events was examined. MIF and its receptor, CD74, were examined in gastric and colon tumors and found to be increased in most tumors with significantly higher expression in tumors from patients with lymph node metastasis. MIF was also found to be highly produced by cancer associated fibroblasts isolated from human tumors compared to fibroblasts from matched normal tissues from uninvolved areas. Fibroblast-produced MIF highly increased GI cancer cell proliferation, which was decreased upon neutralizing MIF or CD74. Chronic MIF treatment led to sustained proliferation and signaling events in non-transformed GI fibroblast cells, which was maintained upon removing MIF treatment for 8 weeks. Additionally, chronic treatment of normal GI cells expressing fibroblast markers for up to 16 weeks with MIF led to a drastic decrease of fibroblast markers with concurrent increase of epithelial markers. Transformation was examined by telomerase and focus forming assays. These results suggest the MIF promotes mesenchymal epithelial transition, cell transformation and tumorigenesis in GI cancers, and thus may be an important link between chronic inflammation and tumorigenesis.
    PLoS ONE 06/2014; 9(6):e98656. DOI:10.1371/journal.pone.0098656 · 3.53 Impact Factor

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