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      Role of MIF in Inflammation and Tumorigenesis

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          MIF has been described as a protein that plays an essential role in both innate and acquired immunity. Previous studies have demonstrated that MIF activates lymphocytes, granulocytes and monocytes/macrophages. Furthermore, MIF can counteract the physiological function of steroids, thus playing a role in immune system regulation. Further evidence for a role of MIF in immunity was obtained in mouse models of autoimmune disorders, where the inhibition of MIF resulted in a more benign disease progression. This observation made MIF an attractive therapeutic target for the treatment of these disorders. Moreover, MIF expression was found to be upregulated in a variety of different tumor cells, a finding that further attracted interest. This review provides an overview of the involvement of MIF in both autoimmune disorders and tumorigenesis and summarizes the molecular action of MIF in this context.

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          Most cited references 50

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          MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment.

          The cytokine macrophage migration inhibitory factor (MIF) plays a critical role in inflammatory diseases and atherogenesis. We identify the chemokine receptors CXCR2 and CXCR4 as functional receptors for MIF. MIF triggered G(alphai)- and integrin-dependent arrest and chemotaxis of monocytes and T cells, rapid integrin activation and calcium influx through CXCR2 or CXCR4. MIF competed with cognate ligands for CXCR4 and CXCR2 binding, and directly bound to CXCR2. CXCR2 and CD74 formed a receptor complex, and monocyte arrest elicited by MIF in inflamed or atherosclerotic arteries involved both CXCR2 and CD74. In vivo, Mif deficiency impaired monocyte adhesion to the arterial wall in atherosclerosis-prone mice, and MIF-induced leukocyte recruitment required Il8rb (which encodes Cxcr2). Blockade of Mif but not of canonical ligands of Cxcr2 or Cxcr4 in mice with advanced atherosclerosis led to plaque regression and reduced monocyte and T-cell content in plaques. By activating both CXCR2 and CXCR4, MIF displays chemokine-like functions and acts as a major regulator of inflammatory cell recruitment and atherogenesis. Targeting MIF in individuals with manifest atherosclerosis can potentially be used to treat this condition.
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            MIF Signal Transduction Initiated by Binding to CD74

            Macrophage migration inhibitory factor (MIF) accounts for one of the first cytokine activities to have been described, and it has emerged recently to be an important regulator of innate and adaptive immunity. MIF is an upstream activator of monocytes/macrophages, and it is centrally involved in the pathogenesis of septic shock, arthritis, and other inflammatory conditions. The protein is encoded by a unique but highly conserved gene, and X-ray crystallography studies have shown MIF to define a new protein fold and structural superfamily. Although recent work has begun to illuminate the signal transduction pathways activated by MIF, the nature of its membrane receptor has not been known. Using expression cloning and functional analysis, we report herein that CD74, a Type II transmembrane protein, is a high-affinity binding protein for MIF. MIF binds to the extracellular domain of CD74, and CD74 is required for MIF-induced activation of the extracellular signal–regulated kinase–1/2 MAP kinase cascade, cell proliferation, and PGE2 production. A recombinant, soluble form of CD74 binds MIF with a dissociation constant of ∼9 × 10−9 K d, as defined by surface plasmon resonance (BIAcore analysis), and soluble CD74 inhibits MIF-mediated extracellular signal–regulated kinase activation in defined cell systems. These data provide a molecular basis for MIF's interaction with target cells and identify it as a natural ligand for CD74, which has been implicated previously in signaling and accessory functions for immune cell activation.
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              MIF as a glucocorticoid-induced modulator of cytokine production.

              Glucocorticoid hormones are important for vital functions and act to modulate inflammatory and immune responses. Yet, in contrast to other hormonal systems, no endogenous mediators have been identified that can directly counter-regulate their potent anti-inflammatory and immunosuppressive properties. Recent investigations of the protein macrophage migration inhibitory factor (MIF), which was discovered originally to be a T-lymphocyte-derived factor, have established it to be a pro-inflammatory pituitary and macrophage cytokine and a critical mediator of septic shock. Here we report the unexpected finding that low concentrations of glucocorticoids induce rather than inhibit MIF production from macrophages. MIF then acts to override glucocorticoid-mediated inhibition of cytokine secretion by lipopolysaccharide (LPS)-stimulated monocytes and to overcome glucocorticoid protection against lethal endotoxaemia. These observations identify a unique counter-regulatory system that functions to control inflammatory and immune responses.

                Author and article information

                S. Karger AG
                October 2008
                15 September 2008
                : 75
                : 3-4
                : 127-133
                aInstitute of Immunology and bDepartment of Neurology, Philipps University Marburg, Marburg, and cDepartment of Neurosurgery, Technical University Munich, Munich, Germany
                155223 Oncology 2008;75:127–133
                © 2008 S. Karger AG, Basel

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                Page count
                References: 69, Pages: 7
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/155223


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