The IL-1-dependent sterile inflammatory response has a substantial caspase-1-independent component that requires cathepsin C.
The IL-1-dependent sterile inflammatory response has a substantial caspase-1-independent component that requires cathepsin C.
复制标题
DOI：
10.4049/jimmunol.1200136
复制
发表时间：
2012-10-01
期刊：
影响因子：
--
通讯作者：
Rock KL
中科院分区：
文献类型：
--
作者：
Kono H;Orlowski GM;Patel Z;Rock KL
对细胞死亡和刺激性晶体的无菌炎症反应在医学上很重要，因为它会引起疾病。虽然这些刺激在结构上是不同的，但它们通过需要细胞因子IL-1的共同途径引起炎症。在体外，炎性小体，特别是其活性半胱天冬酶-1的产生，是产生生物活性IL-1β所绝对需要的。然而，在这里，我们报告说，caspase-1是不需要在体内的IL-1β依赖性无菌炎症反应。此外，我们发现，组织蛋白酶C，它控制的白细胞丝氨酸蛋白酶的活性，能够处理IL-1β，在这个caspase-1的非依赖性途径中发挥了重要作用。缺乏组织蛋白酶C的小鼠对死亡细胞和二氧化硅晶体的炎症反应减少。在不存在组织蛋白酶C的情况下，半胱天冬酶-1变得限速，使得这两种蛋白酶双重缺陷的小鼠在体内产生很少的IL-1β，并且对无菌刺激的炎症反应显著减弱。相反，这些突变小鼠响应于外源性IL-1β产生正常炎症，表明组织蛋白酶C和半胱天冬酶-1在IL-1β上游发挥作用，并且在它们不存在的情况下，成熟IL-1β下游途径的所有组分都是完整的。
The sterile inflammatory response to cell death and irritant crystals is medically important because it causes disease. Although these stimuli are structurally distinct, they cause inflammation through a common pathway that requires the cytokine IL-1. In vitro, the inflammasome, and in particular its generation of active caspase-1, is absolutely required to produce bioactive IL-1β. However, here we report that caspase-1 is not required in vivo for much of the IL-1β-dependent sterile inflammatory response. Furthermore, we find that cathepsin C, which controls the activity of a number of leukocyte serine proteases capable of processing IL-1β, plays a major role in this caspase-1-independent pathway. Mice that are deficient in cathepsin C have reduced inflammatory responses to dying cells and silica crystals. In the absence of cathepsin C, caspase-1 becomes rate-limiting such that mice doubly-deficient in both of these proteases make little IL-1β in vivo and have markedly attenuated inflammatory responses to the sterile stimuli. In contrast, these mutant mice generate normal inflammation in response to exogenous IL-1β, indicating that cathepsin C and caspase-1 function upstream of IL-1β, and in their absence, all components of the pathway downstream of mature IL-1β are intact.
登录
查看更多内容
影响因子：
82.9
作者：
Kawasaki, Yasuhiko;Xu, Zhen-Zhong;Ji, Ru-Rong
通讯作者：
Ji, Ru-Rong
影响因子：
82.9
作者：
Chen, Chun-Jen;Kono, Hajime;Rock, Kenneth L.
通讯作者：
Rock, Kenneth L.
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
56.9
作者：
Dostert, Catherine;Petrilli, Virginie;Tschopp, Jurg
通讯作者：
Tschopp, Jurg