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Essential role for migration inhibitory factor in IL-1 activation of mitogen-activated protein kinases

Macrophage migration inhibitory factor (MIF) is a pluripotential proinflammatory cytokine with a possible role in the pathogenesis of rheumatoid arthritis (RA). MIF is expressed in RA synovium, and directly activates RA synoviocyte gene expression and proliferation, as well as exerting anti-apoptotic effects via inhibition of p53. MIF activates ERK and p38 mitogen-activated protein (MAP) kinase, but evidence for direct activation of NF-κB by MIF is lacking.

Anti-MIF monoclonal antibodies prevent IL-1 activation of fibroblast-like synoviocytes in vitro, implicating MIF in the activation of cells by IL-1. The mechanism of this action of MIF has not been adduced. We studied the activation of signal transduction pathways by IL-1 in cells deficient in MIF. Dermal fibroblasts were cultured from MIF-/- and WT mice, and were exposed to IL-1. MAP kinase and NF-κB activation were studied by Western blotting, electrophoretic mobility shift assay (EMSA), and reporter gene assays.

IL-1 rapidly induced phosphorylation of p38, JNK, and ERK MAP kinases in WT cells. In contrast, MIF-/- cell p38, JNK, and ERK activation in response to IL-1 was reduced. Consistent with this observation, MIF-/-cells were hyporesponsive to IL-1-induced AP-1 DNA binding as measured by EMSA (P = 0.03). IL-1-induced activation of an AP-1 luciferase reporter gene system was also reduced in MIF-/- cells (P = 0.037). Confirming the functional significance of these results, MIF-/-cells were hyporesponsive to IL-1-induced proliferation. In contrast, MIF-/- cells were normally responsive to IL-1-induced MKK3 and MKK7 phosphorylation. No significant difference in NF-κB activation was detected between MIF-/- and WT cells, as measured by cellular IκB content, NF-κB EMSA, or NF-κB luciferase reporter gene assay.

These data demonstrate that MIF is required for cellular MAP kinase responses to IL-1. This represents a novel mechanism of action of MIF in the support of the inflammatory response. The absence of an effect on MKK3/MKK7 or NF-κB suggests the effects may be mediated distally in the signal transduction cascade. Therapeutic MIF antagonism may limit the cellular effects of IL-1.

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Morand, E., Lacey, D., Yang, Y. et al. Essential role for migration inhibitory factor in IL-1 activation of mitogen-activated protein kinases. Arthritis Res Ther 5 (Suppl 3), 127 (2003).

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