MIF-mediated Glucocorticoid Regulation

Glucocorticoids are among the most potent anti-inflammatory and immunosuppressive agents. They inhibit synthesis of numerous cytokines, enzymes involved in the inflammatory process and several cell surface molecules required for immune function. Glucocorticoids mediate these effects through an intracellular receptor GR, which is a member of the steroid/thyroid hormone receptor super family. Glucocorticoid bound to GR translocates to the nucleus where it regulates the expression of GR responsive genes. Ligand bound GR acts by antagonizing the activity of transcription factors, in particular NF-κB, by direct and indirect mechanisms. For example, glucocorticoid bound GR induces the gene transcription of the NF-κB inhibitor, IκB. NF-κB and GR also physically interact, resulting in repression of NF-κB transactivation. GR antagonism is specific to the p65 subunit of the NF-κB heterodimer. GR may also compete with NF-κB for nuclear coactivators, including CBP and p300, thereby reducing transcriptional activation by NF-κB.Macrophage Migration Inhibitory Factor (MIF) is the first mediator to be identified that can counter-regulate the inhibitory effects of glucocorticoids and thus play a critical role in the host control of inflammation and immunity. MIF is secreted from macrophages and T lymphocytes that have been stimulated by glucocorticoids. Once released, MIF overcomes the inhibitory effects of glucocorticoids on cytokine 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-γ production. This observation has identified a pivotal role for MIF within the immune system. In the presence of endotoxin-containing bacteria, there is a TLR4-mediated production of cytokines (including MIF), NO and other mediators. MIF activates a cascade of events including the phosphorylation of ERK, the induction of cytoplasmic PLA2, arachidonic acid and Prostaglandin E2. Thus MIF regulates the anti-inflammatory effects of glucocorticoids. Elevated expression of MIF in the circulation and in the synovial joint has been documented in rheumatoid arthritis.