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* Centre for Inflammatory Diseases, Monash Institute of Medical Research, Clayton, Melbourne, Australia; and
Prince Henry’s Institute of Medical Research, Clayton, Victoria, Australia
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-
B 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 M.-L.T. was supported by a grant from the National Health and Medical Research Council of Australia, and D.A. was supported by a grant from the Swiss National Science Foundation (PBBEA-103004) and the Albert Böni Foundation.
2 M.-L.T. and D.A. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Eric F. Morand, Centre for Inflammatory Diseases, Monash Institute of Medical Research, Monash Medical Centre, Locked Bag No. 29, Clayton, Melbourne, 3168 Australia. E-mail address: eric.morand{at}med.monash.edu.au
4 Abbreviations used in this paper: MIF, macrophage migration inhibitory factor; RA, rheumatoid arthritis; PLA2, phospholipase A2; FLS, fibroblast like-synoviocyte; COX-2, cyclooxygenase-2; WT, wild type; MDF, murine dermal fibroblast; MEF, mouse embryonal fibroblast; MEKK, MAPK/ERK kinase; EGFP, enhanced GFP; MKK3/6, MAPK kinase 3 and 6; AU, arbitrary unit; TRAF2, TNFR-associated factor 2; MFI, mean fluorescence intensity.
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