Immune response MIF-mediated glucocorticoid regulation
MIF-mediated glucocorticoid regulation Glucocorticoids are potent anti-inflammatory and immunosuppressive agents. Theyinhibit synthesis of almost all known cytokines, enzymes involved in the inflammatoryprocess and several cell surface molecules required for immune function.Glucocorticoids mediate these effects via the intracellular receptorGCR-alpha . MIF (macrophage migration inhibitory factor) is a unique counter-regulator ofimmunosuppressive and anti-inflammatory activities of glucocorticoids. MIFis released by macrophages and T-lymphocytes stimulated by glucocorticoids. MIFrelease overcomes the inhibitory effects of glucocorticoids on TNF-alpha,IL-6 and IL-8 production, restores IL-2 and IFN-gammaproduction, and antagonizes the glucocorticoid inhibition of the production ofseveral enzymes and cell surface molecules , , . MIF binds to the transmembrane protein CD74, which is required forMIF -induced activation of extracellular signal-regulated kinaseERK(MARK1/3) cascade. This activation results in activation of several majortranscription factors, such as NF-kB, c-Jun, c-Fos, PU.1and ETS1 . Activated GCR-alpha acts by antagonizing activity of transcription factors, inparticular NF-kB, by direct and indirect mechanisms. GCR-alpha inducesexpression of NF-kB inhibitor NFKBIA . GCR-alphaalso directly interacts with NF-kB, resulting in repression of NF-kBactivation , , . MIF signalingrestores NF-kB activity, thereby upregulating the expression of its target genes.