Caspase-1 Has Both Proinflammatory and Regulatory Properties in Helicobacter Infections, Which Are Differentially Mediated by Its Substrates IL-1β and IL-18
Caspase-1 Has Both Proinflammatory and Regulatory Properties in Helicobacter Infections, Which Are Differentially Mediated by Its Substrates IL-1β and IL-18
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DOI：
10.4049/jimmunol.1103212
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发表时间：
2012-04-15
影响因子：
4.4
通讯作者：
Mueller, Anne
中科院分区：
文献类型：
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作者：
Hitzler, Iris;Sayi, Ayca;Mueller, Anne
促炎半胱氨酸蛋白酶caspase-1在细胞质内通过nod样受体感知多种病原体相关分子模式时被自催化激活。活性caspase-1处理亲il -1 β和亲il -18产生生物活性细胞因子并启动病原体特异性免疫反应。关于胃细菌病原体幽门螺杆菌感染期间caspase-1和炎性体激活的信息很少。在这项研究中，我们利用各种实验感染、疫苗诱导的保护和胃疾病模型，探讨了caspase-1及其细胞因子底物在自发性和疫苗诱导的幽门螺杆菌感染控制以及胃炎和胃癌前驱病变发展中的可能作用。我们发现，由于幽门螺杆菌感染，caspase-1被激活，IL-1 β和IL-18在体内和体外被加工。Caspase-1激活和IL-1信号是有效控制幽门螺杆菌感染的必要条件。IL-1R（-/-）小鼠不能产生保护性免疫，但由于不能产生幽门螺杆菌特异性Th1和Th17应答，因此对幽门螺杆菌相关的胃炎和胃瘤前病变具有保护作用。相比之下，IL-18对于疫苗诱导的保护性免疫是必不可少的，但对于防止过度的T细胞驱动的免疫病理是必不可少的。IL-18（-/-）动物的病理发展强烈加速，并伴有不受限制的Th17反应。总之，我们在这项研究中表明，调节caspase-1底物IL-18的加工和释放抵消了另一种caspase-1底物IL-1 β的促炎活性，从而平衡了感染的控制和防止过度的胃免疫病理。中华免疫学杂志，2012,18(8):394 -3602。
The proinflammatory cysteine protease caspase-1 is autocatalytically activated upon cytosolic sensing of a variety of pathogen-associated molecular patterns by Nod-like receptors. Active caspase-1 processes pro-IL-1 beta and pro-IL-18 to generate the bioactive cytokines and to initiate pathogen-specific immune responses. Little information is available on caspase-1 and inflammasome activation during infection with the gastric bacterial pathogen Helicobacter pylori. In this study, we addressed a possible role for caspase-1 and its cytokine substrates in the spontaneous and vaccine-induced control of Helicobacter infection, as well as the development of gastritis and gastric cancer precursor lesions, using a variety of experimental infection, vaccine-induced protection, and gastric disease models. We show that caspase-1 is activated and IL-1 beta and IL-18 are processed in vitro and in vivo as a consequence of Helicobacter infection. Caspase-1 activation and IL-1 signaling are absolutely required for the efficient control of Helicobacter infection in vaccinated mice. IL-1R(-/-) mice fail to develop protective immunity but are protected against Helicobacter-associated gastritis and gastric preneoplasia as a result of their inability to generate Helicobacter-specific Th1 and Th17 responses. In contrast, IL-18 is dispensable for vaccine-induced protective immunity but essential for preventing excessive T cell-driven immunopathology. IL-18(-/-) animals develop strongly accelerated pathology that is accompanied by unrestricted Th17 responses. In conclusion, we show in this study that the processing and release of a regulatory caspase-1 substrate, IL-18, counteracts the proinflammatory activities of another caspase-1 substrate, IL-1 beta, thereby balancing control of the infection with the prevention of excessive gastric immunopathology. The Journal of Immunology, 2012, 188: 3594-3602.