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      Macrophage migration inhibitory factor: a regulator of innate immunity

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      Nature Reviews. Immunology
      Nature Publishing Group UK

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          Key Points

          • Cytokines are essential effector molecules of innate immunity that initiate and coordinate the cellular and humoral responses aimed, for example, at the eradication of microbial pathogens.

          • Discovered in the late 1960s as a product of activated T cells, the cytokine macrophage migration inhibitory factor (MIF) has been discovered recently to carry out important functions as a mediator of the innate immune system.

          • Constitutively expressed by a broad spectrum of cells and tissues, including monocytes and macrophages, MIF is rapidly released after exposure to microbial products and pro-inflammatory mediators, and in response to stress. After it is released, MIF induces pro-inflammatory biological responses that act as a regulator of immune responses.

          • MIF activates the extracellular signal-regulated kinase 1 (ERK1)/ERK2–mitogen-activated protein kinase pathway, inhibits the activity of JUN activation domain-binding protein 1 (JAB1) — a co-activator of the activator protein 1 (AP1) — upregulates the expression of Toll-like receptor 4 to promote the recognition of endotoxin-expressing bacterial pathogens, sustains pro-inflammatory function by inhibiting p53-dependent apoptosis of macrophages and counter-regulates the immunosuppressive effects of glucocorticoids on immune cells.

          • As a pro-inflammatory mediator, MIF has been shown to be implicated in the pathogenesis of severe sepsis and septic shock, acute respiratory distress syndrome, and several other inflammatory and autoimmune diseases, including rheumatoid arthritis, glomerulonephritis and inflammatory bowel diseases.

          • Given its crucial role as a regulator of innate and acquired immunity, pharmacological or immunological modulation of MIF activity might offer new treatment opportunities for the management of acute and chronic inflammatory diseases.

          Abstract

          For more than a quarter of a century, macrophage migration inhibitory factor (MIF) has been a mysterious cytokine. In recent years, MIF has assumed an important role as a pivotal regulator of innate immunity. MIF is an integral component of the host antimicrobial alarm system and stress response that promotes the pro-inflammatory functions of immune cells. A rapidly increasing amount of literature indicates that MIF is implicated in the pathogenesis of sepsis, and inflammatory and autoimmune diseases, suggesting that MIF-directed therapies might offer new treatment opportunities for human diseases in the future.

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          Most cited references118

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          Mechanisms of TGF-β Signaling from Cell Membrane to the Nucleus

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            Phylogenetic perspectives in innate immunity.

            The concept of innate immunity refers to the first-line host defense that serves to limit infection in the early hours after exposure to microorganisms. Recent data have highlighted similarities between pathogen recognition, signaling pathways, and effector mechanisms of innate immunity in Drosophila and mammals, pointing to a common ancestry of these defenses. In addition to its role in the early phase of defense, innate immunity in mammals appears to play a key role in stimulating the subsequent, clonal response of adaptive immunity.
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              Innate immune sensing and its roots: the story of endotoxin.

              How does the host sense pathogens? Our present concepts grew directly from longstanding efforts to understand infectious disease: how microbes harm the host, what molecules are sensed and, ultimately, the nature of the receptors that the host uses. The discovery of the host sensors--the Toll-like receptors--was rooted in chemical, biological and genetic analyses that centred on a bacterial poison, termed endotoxin.
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                Author and article information

                Contributors
                Thierry.Calandra@hospvd.ch
                Journal
                Nat Rev Immunol
                Nat. Rev. Immunol
                Nature Reviews. Immunology
                Nature Publishing Group UK (London )
                1474-1733
                1474-1741
                2003
                : 3
                : 10
                : 791-800
                Affiliations
                GRID grid.8515.9, ISNI 0000 0001 0423 4662, Division of Infectious Diseases, Department of Internal Medicine, , Centre Hospitalier Universitaire Vaudois, ; Lausanne, CH-1011 Switzerland
                Article
                BFnri1200
                10.1038/nri1200
                7097468
                14502271
                dbba922d-284d-4315-9a47-9d6b72f2cd6b
                © Nature Publishing Group 2003

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

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                © Springer Nature Limited 2003

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