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Review
. 2016 Jul;31(4):634-42.
doi: 10.3904/kjim.2016.098. Epub 2016 May 12.

Macrophage migration inhibitory factor: a potential therapeutic target for rheumatoid arthritis

Kyoung-Woon Kim  1 , Hae-Rim Kim  2
Affiliations
Review

Macrophage migration inhibitory factor: a potential therapeutic target for rheumatoid arthritis

Kyoung-Woon Kim et al. Korean J Intern Med. 2016 Jul.

Abstract

Macrophage migration inhibitory factor (MIF) is originally identified in the culture medium of activated T lymphocytes as a soluble factor that inhibits the random migration of macrophages. MIF is now recognized as a multipotent cytokine involved in the regulation of immune and inf lammatory responses. In rheumatoid arthritis (RA), MIF promotes inf lammatory responses by inducing proinflammatory cytokines and tissue-degrading molecules, promoting the proliferation and survival of synovial fibroblasts, stimulating neutrophil chemotaxis, and regulating angiogenesis and osteoclast differentiation. Expression of MIF in synovial tissue and synovial fluid levels of MIF are elevated in RA patients. Specifically, MIF levels correlate with RA disease activity and high levels are associated with bone erosion. In animal models of RA, the genetic and therapeutic inhibition of MIF has been shown to control inflammation and bone destruction. Based on the role of MIF in RA pathogenesis, small molecular inhibitors targeting it or its receptor pathways could provide a new therapeutic option for RA patients.

Keywords: Arthritis, rheumatoid; Inflammation; Macrophage migration-inhibitory factors; Small molecular inhibitor.

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Conflict of interest statement

No potential conflict of interest relevant to this article was reported.

Figures

Figure 1.
Figure 1.
The role of macrophage migration inhibitory factor (MIF) in the pathogenesis of rheumatoid arthritis (RA). MIF stimulates the release of tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, IL-8, and prostaglandin from macrophages and synovial fibroblasts to induce matrix metalloproteinase (MMP)-1 and MMP-3, phospholipase A2, cyclooxygenase-2, which in RA patients may lead to tissue degradation. MIF also induces MMP-9 and MMP-13 in rat osteoblasts; a similar response may account for the bone destruction and osteoporosis characteristic of RA. MIF induces the production of vascular endothelial growth factor (VEGF) and IL-8 from synovial fibroblasts as well as endothelial tube formation. It also stimulates receptor activator of nuclear factor kB ligand (RANKL) production by RA synovial fibroblasts and causes differentiation of peripheral blood monocytes to mature osteoclasts. PGE2, prostaglandin E2; NO, nitric oxide; VCAM, vascular cell adhesion molecule; ICAM, intercellular adhesion molecule.
Figure 2.
Figure 2.
Signal pathways of migration inhibitory factor (MIF). MIF is induced in response to cytokine production and, after its endocytosis, can interact with intracellular proteins such as Jun activation domain-binding protein-1 (Jab1), thereby down-regulating mitogen-activated protein kinase (MAPK) signals and modulating cellular redox homeostasis. Extracellular MIF binds to the cell surface protein CD74 (invariant chain Ii). CD74 lacks a signal-transducing intracellular domain but interacts with the proteoglycan CD44, which induce the activation of Src-family kinase and MAPK/extracellular signal-regulated kinase (ERK) pathways to either activate the phosphatidylinositol 3-kinase (PI3K)/Akt pathway or initiate the p53-dependent inhibition of apoptosis. MIF also can bind and signal through G-protein-coupled chemokine receptors (GPCRs, e.g., CXCR2 and CXCR4) alone. Complex formation between CXCR2 and CD74, enabling accessory binding, appears to facilitate G protein-coupled receptor (GPCR) activation and the formation of a GPCR-receptor tyrosine kinases like signaling complex to trigger calcium influx and rapid integrin activation.
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References

    1. Montecucco F, Mach F. Common inflammatory mediators orchestrate pathophysiological processes in rheumatoid arthritis and atherosclerosis. Rheumatology (Oxford) 2009;48:11–22. - PubMed
    1. Brennan FM, McInnes IB. Evidence that cytokines play a role in rheumatoid arthritis. J Clin Invest. 2008;118:3537–3545. - PMC - PubMed
    1. Burmester GR, Feist E, Dorner T. Emerging cell and cytokine targets in rheumatoid arthritis. Nat Rev Rheumatol. 2014;10:77–88. - PubMed
    1. David JR. Delayed hypersensitivity in vitro: its mediation by cell-free substances formed by lymphoid cell-antigen interaction. Proc Natl Acad Sci U S A. 1966;56:72–77. - PMC - PubMed
    1. Bernhagen J, Calandra T, Mitchell RA, et al. MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature. 1993;365:756–759. - PubMed

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