Fahmi H, Chaby R
Centre National de la Recherche Scientifique, Université de Paris-Sud, Orsay, France.
Immunol Invest. 1994 Aug;23(4-5):243-58. doi: 10.3109/08820139409066821.
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.
巨噬细胞暴露于内毒素（脂多糖，LPS）会导致其在再次暴露于LPS后结合LPS及产生细胞因子的能力受到抑制。这种现象被称为内毒素耐受或LPS诱导的脱敏。LPS还会刺激巨噬细胞中丝氨酸蛋白酶的分泌，并激活膜磷脂酶。我们研究了胰蛋白酶（一种丝氨酸蛋白酶）和磷脂酰肌醇特异性磷脂酶C（PI-PLC，它可切割诸如CD14等糖基磷脂酰肌醇锚定分子）在LPS诱导的脱敏中的作用。用PI-PLC处理或在蛋白酶抑制剂存在的情况下获得的结果表明，磷脂酶和蛋白酶的激活不参与LPS诱导的脱敏。然而，用胰蛋白酶处理巨噬细胞会消除LPS结合和细胞因子反应。巨噬细胞从这种胰蛋白酶诱导的耐受中恢复（在不重新表达LPS结合位点的情况下恢复TNF-α合成）与LPS诱导的耐受后恢复（在不恢复TNF-α合成的情况下重新表达LPS结合位点）非常不同。这些结果与以下假设一致：在胰蛋白酶降解后，可能会重新合成信号传导LPS受体，而在预先暴露于LPS后，非信号传导LPS受体可能会被内化并循环利用。
