A stress-induced, superoxide-mediated caspase-1 activation pathway causes plasma IL-18 upregulation
A stress-induced, superoxide-mediated caspase-1 activation pathway causes plasma IL-18 upregulation
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DOI：
10.1016/j.immuni.2005.04.006
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发表时间：
2005-06-01
期刊：
影响因子：
32.4
通讯作者：
Okamura, H
中科院分区：
文献类型：
--
作者：
Sekiyama, A;Ueda, H;Okamura, H
已知心理/身体压力会导致自身免疫性疾病和炎症性疾病的复发。为了揭示非炎症应激影响宿主防御的机制，研究了小鼠对制动应激的反应，重点是多功能细胞因子白细胞介素-18（IL-18）的作用。在肾上腺皮质中，应激通过促肾上腺皮质激素（ACTH）和超氧化物介导的caspase-1活化途径诱导IL-18前体蛋白（pro-IL-18），导致pro-IL-18转化为成熟形式，释放到血浆中。caspase-1、活性氧和P38丝裂原活化蛋白激酶（MAPK）的抑制剂抑制了应激诱导的血浆IL-18的积累。这些抑制剂还阻断应激诱导的IL-6表达。这一点，以及在IL-18缺陷小鼠中未诱导IL-6的观察结果，表明应激诱导的IL-6依赖于IL-18。在应激生物体中，IL-18可影响病理和生理过程。控制半胱天冬酶-1活化途径以抑制IL-18水平可以提供针对应激相关的宿主防御破坏的预防手段。
Psychological/physical stresses are known to cause relapses of autoimmune and inflammatory diseases. To reveal a mechanism by which noninflammatory stresses affect host defenses, responses to immobilization stress in mice were investigated, focusing on the role of a multifunctional cytokine, interleukin-18 (IL-18). In the adrenal cortex, the stress induced IL-18 precursor proteins (pro-IL-18) via adrenocorticotropic hormone (ACTH) and a superoxide-mediated caspase-1 activation pathway, resulting in conversion of pro-IL-18 to the mature form, which was released into plasma. Inhibitors of caspase-1, reactive oxygen species, and P38 mitogen-activated protein kinase (MAPK) suppressed stress-induced accumulation of plasma IL-18. These inhibitors also blocked stress-induced IL-6 expression. This, together with the observation that IL-6 was not induced in IL-18-deficient mice, showed that IL-6 induction by stress is dependent on IL-18. In stressed organisms, IL-18 may influence pathological and physiological processes. Controlling the caspase-1 activating pathway to suppress IL-18 levels may provide preventative means against stress-related disruption of host defenses.