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 [1].
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 [2], [3], [4].
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 [5].
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 [6].
GCR-alpha also directly interacts with
NF-kB, resulting in repression of NF-kB
activation [1], [7], [8].
MIF signaling restores NF-kB
activity, thereby upregulating the expression of its target genes [4].
References:
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Negative regulation of nuclear factor-kappaB activation and function by glucocorticoids.
Journal of molecular endocrinology 2002 Apr;28(2):69-78
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Macrophage migration inhibitory factor (MIF): a glucocorticoid counter-regulator within the immune system.
Critical reviews in immunology 1997;17(1):77-88
- Baugh JA, Bucala R
Macrophage migration inhibitory factor.
Critical care medicine 2002 Jan;30(1 Supp):S27-S35
- Aeberli D, Leech M, Morand EF
Macrophage migration inhibitory factor and glucocorticoid sensitivity.
Rheumatology (Oxford, England) 2006 Aug;45(8):937-43
- Leng L, Metz CN, Fang Y, Xu J, Donnelly S, Baugh J, Delohery T, Chen Y, Mitchell RA, Bucala R
MIF signal transduction initiated by binding to CD74.
The Journal of experimental medicine 2003 Jun 2;197(11):1467-76
- Deroo BJ, Archer TK
Glucocorticoid receptor activation of the I kappa B alpha promoter within chromatin.
Molecular biology of the cell 2001 Nov;12(11):3365-74
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Cross-talk between nuclear factor-kappa B and the steroid hormone receptors: mechanisms of mutual antagonism.
Molecular endocrinology (Baltimore, Md.) 1998 Jan;12(1):45-56
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Interaction of glucocorticoid receptor isoforms with transcription factors AP-1 and NF-kappaB: lack of effect of glucocorticoid receptor beta.
Molecular and cellular endocrinology 1999 Nov 25;157(1-2):95-104