Flagellin, a novel mediator of Salmonella-induced epithelial activation and systemic inflammation:: IκBα degradation, induction of nitric oxide synthase, induction of proinflammatory mediators, and cardiovascular dysfunction
Flagellin, a novel mediator of Salmonella-induced epithelial activation and systemic inflammation:: IκBα degradation, induction of nitric oxide synthase, induction of proinflammatory mediators, and cardiovascular dysfunction
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DOI：
10.4049/jimmunol.166.2.1248
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发表时间：
2001-01-15
影响因子：
4.4
通讯作者：
Salzman, AL
中科院分区：
文献类型：
--
作者：
Eaves-Pyles, T;Murthy, K;Salzman, AL
革兰氏阴性脓毒症是由微生物及其产物诱导的促炎基因的作用所介导的。我们报道鞭毛的单体亚单位鞭毛蛋白是沙门氏菌释放的一种有效的促炎物质。鞭毛蛋白(1µg/ml)可诱导肠上皮细胞(IEC)I-kappaBα降解、核因子-kappaB核转位和诱导型一氧化氮合酶(NOS)表达。亲和沙门氏菌突变体不能诱导培养的IEC激活NF-kappaB或产生NO。鞭毛蛋白抗血清可阻断多种革兰氏阴性肠道病原菌(大肠杆菌、沙门氏菌、粘质沙雷氏菌)诱导的IEC产生NO。奇异变形杆菌和普通变形杆菌)。鞭毛蛋白在全身注射时(相当于每只小鼠10杯)，可引起全身炎症，其特征是一系列促炎细胞因子和趋化因子以及诱导型一氧化氮合酶的全身表达。在较高剂量下(类似于300杯/只小鼠)，鞭毛蛋白会引起休克，特征是低血压，降低小鼠的血管收缩能力，并导致死亡。鞭毛蛋白在C3H/HeJ脂多糖耐药小鼠中的作用不减弱，表明Toll样受体-4受体不参与鞭毛蛋白的作用。在内毒素耐药小鼠中，ip。注射S.Dublin鞭毛蛋白或用野生型S.Dublin条件培养基能诱导血清中的干扰素-γ和肿瘤坏死因子-α，而用突变株条件培养液则不起作用。在活菌诱导的感染性休克大鼠的血液中可以检测到鞭毛蛋白，提示革兰氏阴性菌释放的鞭毛蛋白可能通过非依赖于内毒素和Toll样受体-4的途径参与炎症反应。
Gram-negative sepsis is mediated by the actions of proinflammatory genes induced in response to microbes and their products. We report that flagellin, the monomeric subunit of flagella, is a potent proinflammatory species released by Salmonella. Flagellin (1 mug/ml) induces I kappaB alpha degradation, NF-kappaB nuclear translocation, and inducible NO synthase expression in cultured intestinal epithelial cells (IEC). Affagellic Salmonella mutants do not induce NF-kappaB activation or NO production by cultured IEC. Antiserum to flagellin blocks NO production in IEC induced by medium conditioned by a variety of motile Gram-negative enteric pathogens (Escherichia coli, Salmonella muenchen, Serratia marcescens. Proteus mirabilis, and Proteus vulgaris). Flagellin, when injected systemically (similar to 10 mug/mouse), induces systemic inflammation characterized by the systemic expression of a range of proinflammatory cytokines and chemokines and of inducible NO synthase. At higher doses (similar to 300 mug/mouse), flagellin induces shock, characterized by hypotension, reduced vascular contractility in mice, and death. The effects of flagellin do not diminish in C3H/HeJ LPS-resistant mice, indicating that the Toll-like receptor-4 receptor is not involved in flagellin's actions. In LPS-resistant mice, i.p. injection of S. dublin flagellin or medium conditioned by wild-type S. dublin induces serum IFN-gamma and TNF-alpha, whereas medium conditioned by aflagellic mutants has no effect. Flagellin can be detected in the blood of rats with septic shock induced by live bacteria at approximately 1 mug/ml. We propose that flagellin released by Gram-negative pathogens may contribute to the inflammatory response by an LPS- and Toll-like receptor-4-independent pathway.