Release of interleukin-1α or interleukin-1β depends on mechanism of cell death.
Release of interleukin-1α or interleukin-1β depends on mechanism of cell death.
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DOI：
10.1074/jbc.m114.557561
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发表时间：
2014-06-06
期刊：
影响因子：
--
通讯作者：
Brough D
中科院分区：
文献类型：
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作者：
England H;Summersgill HR;Edye ME;Rothwell NJ;Brough D
背景：细胞死亡是通过主要细胞因子IL-1调节炎症的。结果：凋亡刺激诱导巨噬细胞产生caspase-8依赖的IL-1β。坏死性下垂刺激诱导IL-1α的钙蛋白酶依赖性释放。结论：细胞死亡机制决定了IL-1释放的性质和形式。意义：无菌炎症反应可能由细胞死亡机制决定，可能允许选择性干预。细胞因子白细胞介素-1（IL-1）有两种主要的促炎形式，IL-1α和IL-1β，它们是宿主对感染和破坏性无菌炎症反应的核心。将IL-1前体蛋白加工成活性细胞因子通常通过蛋白酶（特别是半胱天冬酶和钙蛋白酶）的活化而发生。这些蛋白酶在细胞死亡中起作用，并且炎症和细胞死亡密切相关，因此我们试图确定细胞死亡途径对IL-1加工和释放的影响。我们发现caspase-8的凋亡调节特异性地诱导IL-1β的加工和释放。相反，坏死性凋亡引起IL-1α的加工和释放，这与IL-1β的加工和释放无关。这些数据表明，表达IL-1的细胞死亡的机制决定了随后的炎症机制的性质。这些见解可以通过选择性靶向疾病期间的细胞死亡机制来改变炎症。
Background: Cell death is a regulator of inflammation via the master cytokine IL-1. Results: Apoptotic stimuli induced a caspase-8-dependent release of IL-1β from macrophages. Necroptotic stimuli induced a calpain-dependent release of IL-1α. Conclusion: Mechanisms of cell death dictate the nature and form of IL-1 release. Significance: Sterile inflammatory responses may be determined by the mechanisms of cell death potentially allowing for selective interventions. The cytokine interleukin-1 (IL-1) has two main pro-inflammatory forms, IL-1α and IL-1β, which are central to host responses to infection and to damaging sterile inflammation. Processing of IL-1 precursor proteins to active cytokines commonly occurs through activation of proteases, notably caspases and calpains. These proteases are instrumental in cell death, and inflammation and cell death are closely associated, hence we sought to determine the impact of cell death pathways on IL-1 processing and release. We discovered that apoptotic regulation of caspase-8 specifically induced the processing and release of IL-1β. Conversely, necroptosis caused the processing and release of IL-1α, and this was independent of IL-1β processing and release. These data suggest that the mechanism through which an IL-1-expressing cell dies dictates the nature of the inflammatory mechanism that follows. These insights may allow modification of inflammation through the selective targeting of cell death mechanisms during disease.