Immune response - MIF-mediated glucocorticoid regulation

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:

1. Almawi WY, Melemedjian OK
   Negative regulation of nuclear factor-kappaB activation and function by glucocorticoids. Journal of molecular endocrinology 2002 Apr;28(2):69-78
2. Calandra T, Bucala R
   Macrophage migration inhibitory factor (MIF): a glucocorticoid counter-regulator within the immune system. Critical reviews in immunology 1997;17(1):77-88
3. Baugh JA, Bucala R
   Macrophage migration inhibitory factor. Critical care medicine 2002 Jan;30(1 Supp):S27-S35
4. Aeberli D, Leech M, Morand EF
   Macrophage migration inhibitory factor and glucocorticoid sensitivity. Rheumatology (Oxford, England) 2006 Aug;45(8):937-43
5. 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
6. 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
7. McKay LI, Cidlowski JA
   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
8. Brogan IJ, Murray IA, Cerillo G, Needham M, White A, Davis JR
   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