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MIF Regulation of Innate Immunity

Macrophage migration inhibitory factor (MIF) is a cytokine that is an integral mediator of the innate immune system. Monocytes and macrophages constitutively express large amounts of MIF, which is rapidly released after exposure to bacterial toxins and cytokines. MIF exerts potent proinflammatory activities and is an important cytokine of septic shock. MIF regulates innate immune responses to endotoxin and gram-negative bacteria by modulating the expression of TLR4 , the signal-transducing molecule of the LPS receptor complex. A receptor complex consisting of a signaling subunit TLR4 and two accessory proteins: MD2 and CD14, recognizes LPS and Gram-negative bacteria...

MIF Regulation of Innate Immunity

Pathway Summary

Macrophage migration inhibitory factor (MIF) is a cytokine that is an integral mediator of the innate immune system. Monocytes and macrophages constitutively express large amounts of MIF, which is rapidly released after exposure to bacterial toxins and cytokines. MIF exerts potent proinflammatory activities and is an important cytokine of septic shock. MIF regulates innate immune responses to endotoxin and gram-negative bacteria by modulating the expression of TLR4 , the signal-transducing molecule of the LPS receptor complex. A receptor complex consisting of a signaling subunit TLR4 and two accessory proteins: MD2 and CD14, recognizes LPS and Gram-negative bacteria. MIF causes optimal TRL4 expression and hence optimal LPS responses in macrophages. Therefore, MIF acts as a specific target for preventing endotoxic shock in cases of Gram-negative sepsis. Deficiency in the MIF shows a profound reduction in the activity of NF-κB and the production of the TNF-α. The reduction is due to the downregulation of TLR4, which is associated with the transcription factor PU.1. TLR4 activates NF-κB and induces the expression of pro-inflammatory cytokines by human monocytic cells. MIF upregulates the expression of TLR4 by macrophages allowing rapid recognition of endotoxin-containing bacteria, which promotes the production of cytokines (including MIF), NO and other mediators. After it is released, MIF activates a cascade of events consisting of the phosphorylation of ERK1 /ERK2 , the induction of cytoplasmic PLA2 , Arachidonic acid, JNK activity and PGE2. Through the generation of Oxidoreductase activity and COX2 , MIF prevents activation-induced apoptosis mediated by the oxidative burst and by p53.The role of p53-dependent apoptosis in the immune system is known to be significant during B- and T-lymphopoiesis, in protection from genotoxic stressors and in sustaining monocyte or macrophage activation responses. Overexpression of MIF inhibits p53-dependent apoptosis and protects macrophages from NO-induced apoptosis. The inhibition of p53 by MIF is critical for the development various tumors. MIF inhibits p53-dependent cell cycle arrest, extend fibroblast life span, and decrease NO-induced apoptosis in macrophages. NO strongly induces the p53-dependent transcription in cells. Arachidonic acid and the expression of Cox-2 negatively regulate NO-mediated p53 accumulation and apoptosis in macrophages. Macrophage apoptosis induced by NO was almost completely suppressed by overexpression of MIF. Cox-2 activity by MIF is required for the MIF-mediated suppression of p53 accumulation and macrophage apoptosis in response to NO challenge. The conversion of Arachidonic acid into PGE2 is a critical component of MIF-mediated inhibition of p53-dependent macrophage apoptosis.MIF modulates cytosolic PLA2 activity via ERK1/ERK2 dependent pathway. MIF-stimulated cytoplasmic PLA2 activation led to the production of Arachidonic acid in a time and concentration-dependent fashion. Arachidonic acid release is the first step in the downstream synthesis of prostaglandins and leukotrienes, which have important pro-inflammatory and growth-regulating properties. Arachidonic acid also stimulates the JNK, which in turn activates cell growth through the modulation of the AP1, NF-κB, or p53 transcriptional activity and produces NO. The LPS-induced apoptotic response in macrophages requires the production of nitric oxide (NO), the intracellular accumulation of the tumor suppressor gene product p53. The sustained activation of ERK1 and ERK2 and subsequent Arachidonic acid release by cytoplasmic PLA2 are important features of the immunoregulatory and intracellular signaling events initiated by MIF and provide the first insight into the mechanisms that underlie the pro-proliferative and inflammatory properties of this mediator.

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