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
c-Fos, PU.1 and
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 .
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