Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Macrophage migration inhibitory factor (MIF) is a secreted protein that activates macrophages, neutrophils and T cells, and is implicated in sepsis, adult respiratory distress syndrome and rheumatoid arthritis. The mechanism of MIF function, however, is unknown. The three-dimensional structure of MIF is unlike that of any other cytokine, but bears striking resemblance to three microbial enzymes, two of which possess an N-terminal proline that serves as a catalytic base. Human MIF also possesses an N-terminal proline (Pro-1) that is invariant among all known homologues. Multiple sequence alignment of these MIF homologues reveals additional invariant residues that span the entire polypeptide but are in close proximity to the N-terminal proline in the folded protein. We find that p-hydroxyphenylpyruvate, a catalytic substrate of MIF, binds to the N-terminal region and interacts with Pro-1. Mutation of Pro-1 to a glycine substantially reduces the catalytic and cytokine activity of MIF. We suggest that the underlying biological activity of MIF may be based on an enzymatic reaction. The identification of the active site should facilitate the development of structure-based inhibitors.
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PMID:Direct link between cytokine activity and a catalytic site for macrophage migration inhibitory factor. 964 24

Identification of new therapeutic targets for the management of septic shock remains imperative as all investigational therapies, including anti-tumor necrosis factor (TNF) and anti-interleukin (IL)-1 agents, have uniformly failed to lower the mortality of critically ill patients with severe sepsis. We report here that macrophage migration inhibitory factor (MIF) is a critical mediator of septic shock. High concentrations of MIF were detected in the peritoneal exudate fluid and in the systemic circulation of mice with bacterial peritonitis. Experiments performed in TNFalpha knockout mice allowed a direct evaluation of the part played by MIF in sepsis in the absence of this pivotal cytokine of inflammation. Anti-MIF antibody protected TNFalpha knockout from lethal peritonitis induced by cecal ligation and puncture (CLP), providing evidence of an intrinsic contribution of MIF to the pathogenesis of sepsis. Anti-MIF antibody also protected normal mice from lethal peritonitis induced by both CLP and Escherichia coli, even when treatment was started up to 8 hours after CLP. Conversely, co-injection of recombinant MIF and E. coli markedly increased the lethality of peritonitis. Finally, high concentrations of MIF were detected in the plasma of patients with severe sepsis or septic shock. These studies define a critical part for MIF in the pathogenesis of septic shock and identify a new target for therapeutic intervention.
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PMID:Protection from septic shock by neutralization of macrophage migration inhibitory factor. 1065 4

The precise regulatory mechanisms of amplification and downregulation of the pro- and anti-inflammatory cytokines in the inflammatory response have not been fully delineated. Although activated protein C (APC) and its precursor protein C (PC) have recently been reported to be promising therapeutic agents in the management of meningococcal sepsis, direct evidence for the anti-inflammatory effect remains scarce. We report that APC inhibits in vitro the release of tumor necrosis factor (TNF) and macrophage migration inhibitory factor (MIF), two known cytokine mediators of bacterial septic shock, from lipopolysaccharide (LPS)-stimulated human monocytes. The THP-1 monocytic cell line, when stimulated with LPS and concomitant APC, exhibited a marked reduction in the release of TNF and MIF protein in a concentration-dependent manner compared to cells stimulated with LPS alone. This effect was observed only when incubations were performed in serum-free media, but not in the presence of 1-10% serum. Serum-mediated inhibition could only be overcome by increasing APC concentrations to far beyond physiological levels, suggesting the presence of endogenous serum-derived APC inhibitors. Inhibition of MIF release by APC was found to be independent of TNF, as stimulation of MIF release by LPS was unaltered in the presence of anti-TNF antibodies. Our data confirm that the suggested anti-inflammatory properties of APC are due to direct inhibition of the release of the pro-inflammatory monokine TNF, and imply that the anti-inflammatory action of APC is also mediated via inhibition of MIF release.
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PMID:Activated protein C inhibits tumor necrosis factor and macrophage migration inhibitory factor production in monocytes. 1102 25

Recent advances suggest that toll-like receptors, various cytokines, cicosanoids, free radicals and macrophage migration inhibitory factor (MIF) play an important role in the pathobiology of septicemia and septic shock. Anti-MIF antibodies can decrease the plasma concentrations of tumor necrosis factor (TNF), lower bacterial circulating counts and enhance survival of animals with septicemia and septic shock. Monocyte expression of MHC-class II antigens, neutrophil expression of the integrin CD11b/CD18 and neutrophil activation can be related to the development of, and/or recovery from, post-operative sepsis. Thus, biological variations in the response of an individual to a given stimulus, appears to determine his/her ability or inability to develop and also recover from sepsis and septic shock. This suggests that it may be possible to predict the development of septicemia and septic shock in a given individual and take appropriate action both to prevent and treat them adequately.
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PMID:Critical advances in septicemia and septic shock. 1109 8

Diabetic ketoacidosis and moderate degree of hyperglycemia can be managed by glucose-insulin-potassium (GIK) regimen. The GIK regimen is also useful in the treatment of acute myocardial infarction (AMI). But, the exact mechanism(s) of the beneficial action of GIK regimen is not known. I suggest that glucose-insulin can suppress the secretion and antagonize the harmful effects of tumor necrosis factor alpha (TNF alpha) and macrophage migration inhibitory factor (MIF). If this is true, it suggests that GIK regimen may be useful in septicemia and septic shock, and other inflammatory conditions such as ulcerative colitis, Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus and cancer, conditions in which TNF alpha and MIF appear to play a major role.
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PMID:Newer uses of glucose-insulin-potassium regimen. 1120 54

The importance of the macrophage in innate immunity is underscored by its secretion of an array of powerful immunoregulatory and effector molecules. We report herein that macrophage migration inhibitory factor (MIF), a product of activated macrophages, sustains macrophage survival and function by suppressing activation-induced, p53-dependent apoptosis. Endotoxin administration to MIF(-/-) mice results in decreased macrophage viability, decreased proinflammatory function, and increased apoptosis when compared with wild-type controls. Moreover, inhibition of p53 in endotoxin-treated, MIF-deficient macrophages suppresses enhanced apoptosis and restores proinflammatory function. MIF inhibits p53 activity in macrophages via an autocrine regulatory pathway, resulting in a decrease in cellular p53 accumulation and subsequent function. Inhibition of p53 by MIF coincides with the induction of arachidonic acid metabolism and cyclooxygenase-2 (Cox-2) expression, which is required for MIF regulation of p53. MIF's effect on macrophage viability and survival provides a previously unrecognized mechanism to explain its critical proinflammatory action in conditions such as sepsis, and suggests new approaches for the modulation of innate immune responses.
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PMID:Macrophage migration inhibitory factor (MIF) sustains macrophage proinflammatory function by inhibiting p53: regulatory role in the innate immune response. 1175 71

Over the past year, human studies have confirmed and expanded the involvement of macrophage migration inhibitory factor (MIF) in a number of diseases that had originally been studied in animals. In addition to sepsis, rheumatoid arthritis, glomerulonephritis and inflammatory lung disease, elevated MIF levels have been described in patients suffering from ulcerative colitis, inflammatory neurological diseases and cancer. Cellular studies indicate that in addition to macrophages, MIF affects the activities of CD4+ and CD8+ T cells, natural killer cells, fibroblasts and endothelial cells, actions that may explain the contribution of MIF to inflammatory diseases and cancer. Molecular studies have identified direct interactions between MIF and several intracellular regulatory proteins (Jab1, PAG and p53) that control cellular growth and proliferation; however, how interactions with these proteins fit into a general scheme to explain MIF's biological activity has not been elucidated. The three-dimensional structure of MIF has offered some surprising clues and if the potential enzymatic sites identified are involved with MIF-associated diseases, they may provide good targets for therapeutic intervention.
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PMID:Glucocorticoid counter regulation: macrophage migration inhibitory factor as a target for drug discovery. 1175 24

Macrophages are pivotal effector cells of the innate immune system, which is vital for recognizing and eliminating invasive microbial pathogens. When microbial products bind to pathogen-recognition receptors, macrophages become activated and release a broad array of cytokines that orchestrate the host innate and adaptive immune responses. Initially identified as a T-cell cytokine, macrophage migration inhibitory factor (MIF) is also a macrophage cytokine and an important mediator of inflammation and sepsis. Here we report that MIF is an essential regulator of macrophage responses to endotoxin (lipopolysaccharide) and Gram-negative bacteria. Compared with wild-type cells, MIF-deficient macrophages are hyporesponsive to lipopolysaccharide and Gram-negative bacteria, as shown by a profound reduction in the activity of NF-kappaB and the production of tumour-necrosis factor-alpha. This reduction is due to a downregulation of Toll-like receptor 4 (TLR4), the signal-transducing molecule of the lipopolysaccharide receptor complex, and is associated with decreased activity of transcription factor PU.1, which is required for optimal expression of the Tlr4 gene in myeloid cells. These findings identify an important role for MIF in innate immunity and provide a molecular basis for the resistance of MIF-deficient mice to endotoxic shock.
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PMID:MIF regulates innate immune responses through modulation of Toll-like receptor 4. 1178 66

Macrophage migration inhibitory factor (MIF) has been proposed to be the physiologic counter-regulator of glucocorticoid action within the immune system. In this role, MIF's position within the cytokine cascade is to act in concert with glucocorticoids to control both the "set point" and the magnitude of the inflammatory response. As well as overriding the immunosuppressive effects of glucocorticoids, it is now well established that MIF has a direct proinflammatory role in inflammatory diseases, such as sepsis, rheumatoid arthritis, and glomerulonephritis. The functions of MIF within the immune system are both unique and diverse, and although a unified molecular mechanism of action remains to be elucidated, there have been significant advances in our understanding of how MIF affects cellular processes. This review discusses the pathogenic role of MIF in inflammatory disease and highlights the novel structural, functional, and mechanistic properties of MIF.
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PMID:Macrophage migration inhibitory factor. 1178 58

Macrophage migration inhibitory factor (MIF) has been proposed to be the physiologic counter-regulator of glucocorticoid action within the immune system. In this role, MIF's position within the cytokine cascade is to act in concert with glucocorticoids to control both the "set point" and the magnitude of the inflammatory response. As well as overriding the immunosuppressive effects of glucocorticoids, it is now well established that MIF has a direct proinflammatory role in inflammatory diseases, such as sepsis, rheumatoid arthritis, and glomerulonephritis. The functions of MIF within the immune system are both unique and diverse, and although a unified molecular mechanism of action remains to be elucidated, there have been significant advances in our understanding of how MIF affects cellular processes. This review discusses the pathogenic role of MIF in inflammatory disease and highlights the novel structural, functional, and mechanistic properties of MIF.
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PMID:Macrophage migration inhibitory factor. 1189 4


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