MIF Mediated Glucocorticoid Regulation
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MIF Mediated Glucocorticoid Regulation
Glucocorticoids are among the most potent anti-inflammatory and immunosuppressive agents. They inhibit synthesis of almost all known Cytokines, enzymes involved in the inflammatory process and of several cell surface molecules required for immune function. Glucocorticoids mediate these effects through an intracellular receptor, the GR (Glucocorticoid Receptor), a member of the steroid/thyroid hormone receptor super family. The Glucocorticoid hormones affect the metabolism of carbohydrates, proteins, and lipids in a manner nearly opposite to that of Insulin and influence a wide variety of other vital functions, including nucleic acid synthesis, maintenance of blood pressure, inflammatory reactions and the capacity to cope with stress. Data presently indicates that MIFs (Macrophage Migration Inhibitory Factor) position within the cytokine cascade is to act in concert with Glucocorticoids to control the set point and magnitude of the immune and inflammatory response.

MIF has the unique property of being released from macrophages and T lymphocytes that have been stimulated by Glucocorticoids. Once released, MIF overcomes the inhibitory effects of Glucocorticoids on TNF-Alpha, IL-1Beta, IL-6, and IL-8 production by LPS-stimulated monocytes in vitro and suppresses the protective effects of steroids against lethal endotoxemia in vivo. MIF also antagonizes Glucocorticoid inhibition of T-cell proliferation in vitro by restoring IL-2 and Ifn-Gamma production. This observation has identified a pivotal role for MIF within the immune system and fills an important gap in our understanding of the control of inflammatory and immune responses. Glucocorticoids have long been considered to be an integral component of the stress response to infection or tissue invasion and serve to modulate inflammatory and immune responses. MIF is the first mediator to be identified that can counter-regulate the inhibitory effects of Glucocorticoids and thus plays a critical role in the host control of inflammation and immunity (Ref.1). NF-KappaB and the GR physically interact, resulting in repression of NF-KappaB transactivation. The GR antagonism is specific to the p65 subunit of NF-KappaB heterodimer, whereas multiple domains of GR are essential to repress p65-mediated transactivation. GR effectively inhibits p65 transactivation (Ref.2).

MIF upregulates the expression of TLR4 by macrophages allowing rapid recognition of endotoxin-containing bacteria, which promotes the production of Cytokines (including MIF), NO (Nitric Oxide) and other mediators. After it is released, MIF activates a cascade of events consisting of the phosphorylation of ERK1 (Extracellular Signal-Regulated Kinase-1) /ERK2 (Extracellular Signal-Regulated Kinase-2), the induction of cytoplasmic PLA2 (Phospholipase-A2), Arachidonic acid, JNK (Jun N-Terminal Kinase) activity and PGE2 (Prostaglandin E2). Through the generation of Oxidoreductase activity and COX2 (Cyclooxygenase-2). The Glucocorticoid inhibits PLA2 (Ref.3). Glucocorticoids inhibit NF-KappaB activity in some tissues by elevating the levels of I-KappaB-Alpha. Glucocorticoids activate the I-KappaB-Alpha promoter in human cells containing the GR (Glucocorticoid Receptor). MIF inhibits the I-KappaB degradation and thus antagonizes the immune and inflammatory gene expression (Ref.4).

MIF acts to override Glucocorticoid-mediated inhibition of Cytokine secretion by lipopolysaccharide (LPS)-stimulated monocytes and to overcome Glucocorticoid protection against lethal endotoxemia (Ref.5). Glucocorticoids act through the GR to enhance or repress transcription of Glucocorticoid responsive genes depending on the promoter context and cellular background (Ref.6). MIF counter-regulates the inhibitory effects of Glucocorticoids on immune cell activation. MIF is released from cells in response to Glucocorticoids, certain pro-inflammatory stimuli, and mitogens and acts to regulate Glucocorticoid action on the ensuing inflammatory response. MIF regulates cytosolic PLA2 (Phospholipase-A2) activity via a PKA (Protein Kinase-A) and ERK dependent pathway. Glucocorticoid suppresses cytokine-induced cytoplasmic PLA2 activity and arachidonic acid release can be reversed by the addition of recombinant MIF (Ref.7).

The activated GR acts by antagonizing the activity of transcription factors, in particular NF-KappaB, by direct and indirect mechanisms. GCs induced the gene transcription and protein synthesis of the NF-KappaB inhibitor, I-KappaB-Alpha. Activated GR also antagonized NF-KappaB activity through protein-protein interaction involving direct complexing with, and inhibition of NF-KappaB binding to DNA (Simple Model), or association with NF-KappaB bound to KappaB DNA site. GR may compete with NF-KappaB for nuclear coactivators, including CBP and p300, thereby reducing and inhibiting transcriptional activation by NF-KappaB (Ref.8).

MIF is a potent pro-inflammatory cytokine and regulates the anti-inflammatory effects of Glucocorticoids. An important role for MIF within the cytokine cascade is to act in concert with endogenous Glucocorticoids to control the set-point and magnitude of the inflammatory response. Elevated expression of MIF in the circulation and in the synovial joint has been documented in rheumatoid arthritis.