Regulation of IL-1 and TNF Receptor Expression and Function by Endogenous Macrophage Migration Inhibitory Factor

Centre for Inflammatory Diseases, Monash Institute of Medical Research, Monash Medical Center, Clayton, Melbourne 3168, Australia.
The Journal of Immunology (Impact Factor: 4.92). 11/2006; 177(7):4818-25. DOI: 10.4049/jimmunol.177.7.4818
Source: PubMed


Macrophage migration inhibitory factor (MIF) has a key role in regulation of innate and adaptive immunity and is implicated in sepsis, tumorigenesis, and autoimmune disease. MIF deficiency or immunoneutralization leads to protection against fatal endotoxic, exotoxic, and infective shock, and anti-inflammatory effects in other experimental models of inflammatory disease. We report a novel regulatory role of MIF in type 1 IL-1R and p55 TNFR expression and function. Compared with wild-type cells, MIF-deficient cells were hyporesponsive to IL-1- and TNF-induced MAPK activity, AP-1 activity, and cellular proliferation, while NF-kappaB function was preserved. Hyporesponsiveness of MIF-deficient cells was associated with down-regulation of cytokine receptor expression, which was restored by reconstitution of either an upstream kinase of MAPK, MAPK/ERK kinase, or MIF. These data suggest that endogenous MIF is required for cytokine activation of MAPK/AP-1 and cytokine receptor expression. This autocrine regulatory pathway defines an important amplifying role of endogenous MIF in cytokine-mediated immune and inflammatory diseases and provides further molecular evidence for the critical role of MIF in cellular activation.

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Available from: Daniel Aeberli
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    • "MIF, a classic pro-inflammatory cytokine and a pivotal regulator of innate immunity, promotes innate and adaptive immune responses through the activation of macrophages and T cells [25,26]. Moreover, it directly inhibits the immunosuppressive actions of glucocorticoids [27] through the suppression of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) [28-30]. MKP-1, which is induced by glucocorticoids, inactivates the proinflammatory ERK1/2, JNK, and p38 pathways. "
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    ABSTRACT: Background Marek’s disease virus (MDV) is a highly cell-associated oncogenic α-herpesvirus that causes a disease characterised by T-cell lymphomas. The pathogenesis, or the nature of the interaction of the virus and the host, in the thymus are still unclear. Results In this study, we identified 119 differentially expressed proteins using two-dimensional electrophoresis and mass spectrometry from the thymuses of chickens infected with the RB1B strain of MDV. These differentially expressed proteins were found mainly at 21, 28 and 35 days post-infection. More than 20 of the differentially expressed proteins were directly associated with immunity, apoptosis, tumour development and viral infection and replication. Five of these proteins, ANXA1, MIF, NPM1, OP18 and VIM, were further confirmed using real-time PCR. The functional associations and roles in oncogenesis of these proteins are discussed. Conclusions This work provides a proteomic profiling of host responses to MDV in the thymus of chickens and further characterises proteins related to the mechanisms of MDV oncogenesis and pathogenesis.
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    • "Moreover, UVB irradiation enhances the expression of MIF in the epidermis, and MIF Tg mice showed higher levels of MIF mRNA expression after UVB exposure (Shimizu, 1999c). Once released, MIF acts as a proinflammatory cytokine to induce the expression of other inflammatory cytokines, including IL-1, IL-6 and TNF-α (Toh et al., 2006, Sanchez-Zamora et al., 2010, Donnelly, 1997). Since the intense inflammation in the skin in response to UVB irradiation was found to correlate with the early onset of carcinogenesis and a higher incidence of tumors after chronic UVB exposure, this finding confirms the likely role of MIF in this process. "

    Full-text · Chapter · Nov 2011
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    • "This suggests that MIF interacts not only with VEGF but also with other inflammatory cytokines in our ocular chemical burn model. MIF was previously determined to induce TNF-α and IL-1 β expression from the peripheral blood mononuclear cells [34]. Additionally, TNF-α was reported to induce the secretion of MIF from dendritic cells and ovarian cancer cells [35,36]. "
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    ABSTRACT: To evaluate the role of macrophage migration inhibitory factor (MIF) in the wound healing process following severe chemical burns to the ocular surface. Chemical burning of the ocular surface was induced in mice (C57BL/6) via the application of 0.1 M NaOH. Macrophage migration inhibitory factor (MIF), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) mRNA expression in the ocular surface and lacrimal gland was evaluated via real-time reverse transcription PCR on days 2, 7, and 30 after induction of the chemical burn. The expression of MIF protein in the ocular surface and lacrimal gland was evaluated via western blot analysis. Immunohistochemical staining was conducted to detect MIF and vasculoendothelial growth factor in the cornea during the wound healing process. The angiogenic role of MIF was further evaluated using an 8-0 polyglactin suture technique to induce corneal neovascularization. MIF, TNF-α, and IL-1β mRNA expression were elevated significantly in the ocular surface up to day 30 after chemical burn induction. TNF-α alone was elevated in the lacrimal gland. MIF protein elevation was confirmed via western blot analysis, and the spatial similarity of MIF and VEGF expression in the cornea was noted during the wound healing process. 8-0 polyglactin sutures soaked in MIF induced significantly higher numbers of new vessels on the mouse cornea after 7 days (p=0.003, Mann-Whitney test). These findings indicate that MIF performs a crucial role in wound healing on the ocular surface after the induction of chemical burns.
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