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      MIF Signal Transduction Initiated by Binding to CD74

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          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 PGE 2 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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          Most cited references 61

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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.
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            Mechanism of a reaction in vitro associated with delayed-type hypersensitivity.

            The cell type responsible for inhibition by antigen of migration in vitro of peritoneal exudate cells obtained from tuberculin-hypersensitive guinea pigs was studied. Exudate populations were separated into component cell types, the lymphocyte and the macrophage. Peritoneal lymphocytes from sensitive donors were the immunologically active cells in this system, the macrophages, being merely indicator cells which migrate. Sensitized peritoneal lymphocyte populations, upon interaction with specific antigen in vitro, elaborated into the medium a soluble material capable of inhibiting migration of normal exudate cells.
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              The macrophage is an important and previously unrecognized source of macrophage migration inhibitory factor

              For over 25 years, the cytokine known as macrophage migration inhibitory factor (MIF) has been considered to be a product of activated T lymphocytes. We recently identified the murine homolog of human MIF as a protein secreted by the pituitary in response to endotoxin administration. In the course of these studies, we also detected MIF in acute sera obtained from endotoxin-treated, T cell- deficient (nude), and hypophysectomized mice, suggesting that still more cell types produce MIF. Here, we report that cells of the monocyte/macrophage lineage are an important source of MIF in vitro and in vivo. We observed high levels of both preformed MIF protein and MIF mRNA in resting, nonstimulated cells. In the murine macrophage cell line RAW 264.7, MIF secretion was induced by as little as 10 pg/ml of lipopolysaccharide (LPS), peaked at 1 ng/ml, and was undetectable at LPS concentrations > 1 microgram/ml. A similar stimulation profile was observed in LPS-treated peritoneal macrophages; however, higher LPS concentrations were necessary to induce peak MIF production unless cells had been preincubated with interferon gamma (IFN-gamma). In RAW 264.7 macrophages, MIF secretion also was induced by tumor necrosis factor alpha (TNF-alpha) and IFN-gamma, but not by interleukins 1 beta or 6. Of note, MIF-stimulated macrophages were observed to secrete bioactive TNF-alpha. Although previously overlooked, the macrophage is both an important source and an important target of MIF in vivo. The activation of both central (pituitary) and peripheral (macrophage) sources of MIF production by inflammatory stimuli provides further evidence for the critical role of this cytokine in the systemic response to tissue invasion.

                Author and article information

                J Exp Med
                The Journal of Experimental Medicine
                The Rockefeller University Press
                2 June 2003
                : 197
                : 11
                : 1467-1476
                [1 ]Department of Internal Medicine, Section of Rheumatology, Yale University School of Medicine, New Haven, CT 06520
                [2 ]The North-Shore–Long Island Jewish Research Institute, Manhasset, NY 11030
                [3 ]Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland
                [4 ]Core Facility, Memorial Sloan-Kettering Cancer Center, New York, NY 10031
                [5 ]Department of Pharmacology, Mount Sinai School of Medicine, New York, NY 10029
                [6 ]J.G. Brown Cancer Center, University of Louisville, Louisville, KY 40202
                Author notes

                Address correspondence to Richard Bucala, Dept. of Medicine, Section of Rheumatology, Yale University School of Medicine, 333 Cedar St., P.O. Box 208031, New Haven, CT 06520-8031. Phone: 203-737-1453; Fax: 203-785-7053; E-mail: richard.bucala@ 123456yale.edu

                Copyright © 2003, The Rockefeller University Press


                macrophage migration inhibitory factor, cytokine, receptor, map kinase, invariant chain


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