Implication of Toll-like receptor and tumor necrosis factor alpha signaling in septic shock.
Septic shock is initiated by a systemic inflammatory response to microbial infection that frequently leads to impaired perfusion and multiple organ failure. Because of its high risk of death, septic shock is a major problem particularly for patients in the intensive care unit. In general, bacterial lipopolysaccharide (LPS) is a strong activator of various immune responses and stimulates monocytes/macrophages to release a variety of inflammatory cytokines. However, overproduction of inflammatory factors in response to bacterial infections is known to cause septic shock, similar to that induced by LPS. Studies of LPS-signaling pathways and downstream inflammatory cytokines may have critical implications in the treatment of sepsis. In recent years, there has been significant progress in understanding the signaling pathways activated by LPS and its receptor Toll-like receptor 4 (TLR4), as well as by tumor necrosis factor alpha (TNFalpha), a potent inflammatory cytokine induced by LPS stimulation. This review briefly summarizes our current knowledge of these signaling pathways and critical signal transducers. Characterization of key signal transducers may allow us to identify tractable, novel targets for the therapeutic interventions of sepsis.
Lin
Wen-Jye
WJ
The Campbell Family Institute for Breast Cancer Research, University Health Network and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 2C1.
Yeh
Wen-Chen
WC
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D053592:Interleukin-1 Receptor-Associated Kinases; D008070:Lipopolysaccharides / Q000378:metabolism; D008264:Macrophages / Q000166:cytology; D008954:Models, Biological; D009000:Monocytes / Q000166:cytology; D053594:Myeloid Differentiation Factor 88; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D012772:Shock, Septic / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D016207:Cytokines; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; D011494:Protein Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D053592:Interleukin-1 Receptor-Associated Kinases