Differential recovery of macrophages from endotoxin-tolerant states elicited by lipopolysaccharide and enzymatic treatments.
Exposure of macrophages to endotoxin (lipopolysaccharide, LPS) leads to a suppression of their capacity to bind LPS and to produce cytokines after reexposure to LPS. This phenomenon is termed endotoxin tolerance, or LPS-induced desensitization. LPS also stimulates the secretion of serine proteases in macrophages, and activates membrane phospholipases. We have investigated the role of trypsin (a serine protease) and of a phosphatidylinositol-specific phospholipase C (PI-PLC, which cleaves GPI-anchored molecules such as CD14), on LPS-induced desensitization. The results obtained by treatment with PI-PLC or in the presence of protease inhibitors, suggested that activation of phospholipases and proteases are not involved in LPS-induced desensitization. However, trypsin treatment of macrophages abolished both LPS binding and cytokine responses. The recovery of macrophages from this trypsin-induced tolerance (restoration of TNF-alpha synthesis without reexpression of LPS-binding sites) was very different from that following LPS-induced tolerance (reexpression of LPS-binding sites without restoration of TNF-alpha synthesis). The results are consistent with the hypothesis that signaling LPS-receptors might be synthesized de novo after trypsin degradation, whereas non-signaling LPS-receptors might be internalized and recycled after preexposure to LPS.
Centre National de la Recherche Scientifique, Université de Paris-Sud, Orsay, France.
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Fahmi
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Chaby
D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D004731:Endotoxins / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology*; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D054801:Phosphoinositide Phospholipase C; D010727:Phosphoric Diester Hydrolases / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D014357:Trypsin / Q000494:pharmacology
D016207:Cytokines; D004731:Endotoxins; D008070:Lipopolysaccharides; D011480:Protease Inhibitors; D010727:Phosphoric Diester Hydrolases; D054801:Phosphoinositide Phospholipase C; D014357:Trypsin; D043265:Phosphatidylinositol Diacylglycerol-Lyase