MIF-mediated glucocorticoid regulation
Glucocorticoids are potent anti-inflammatory and immunosuppressive agents. They inhibit synthesis of almost all known cytokines, enzymes involved in the inflammatory process and several cell surface molecules required for immune function. Glucocorticoids mediate these effects via the intracellular receptor GCR-alpha .
MIF (macrophage migration inhibitory factor) is a unique counter-regulator of immunosuppressive and anti-inflammatory activities of glucocorticoids. MIF is released by macrophages and T-lymphocytes stimulated by glucocorticoids. MIF release overcomes the inhibitory effects of glucocorticoids on TNF-alpha, IL-6 and IL-8 production, restores IL-2 and IFN-gamma production, and antagonizes the glucocorticoid inhibition of the production of several enzymes and cell surface molecules , , .
MIF binds to the transmembrane protein CD74, which is required for MIF -induced activation of extracellular signal-regulated kinase ERK(MARK1/3) cascade. This activation results in activation of several major transcription factors, such as NF-kB, c-Jun, c-Fos, PU.1 and ETS1 .
Activated GCR-alpha acts by antagonizing activity of transcription factors, in particular NF-kB, by direct and indirect mechanisms. GCR-alpha induces expression of NF-kB inhibitor NFKBIA . GCR-alpha also directly interacts with NF-kB, resulting in repression of NF-kB activation , , . MIF signaling restores NF-kB activity, thereby upregulating the expression of its target genes .