Endoplasmic reticulum stress is sufficient for the induction of IL-1β production via activation of the NF-κB and inflammasome pathways
Endoplasmic reticulum stress is sufficient for the induction of IL-1β production via activation of the NF-κB and inflammasome pathways
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DOI：
10.1177/1753425913508593
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发表时间：
2014-11-01
期刊：
影响因子：
3.2
通讯作者：
Chung, Hun Taeg
中科院分区：
文献类型：
--
作者：
Kim, Sena;Joe, Yeonsoo;Chung, Hun Taeg
代谢综合征和肥胖等病理生理状态的潜在机制包括内质网（ER）应激和异常炎症反应。ER应激是由应激条件下错误折叠蛋白质的积累引起的。然而，ER应激调节炎症的确切机制仍不完全清楚。在这项研究中，我们假设ER应激单独可以代表一个足够的信号调节炎性小体依赖性细胞因子的反应。我们发现，几种ER应激诱导化学物质和游离脂肪酸棕榈酸酯可以触发各种细胞类型中的IL-1分泌，包括单核细胞白血病细胞、原代巨噬细胞和分化的脂肪细胞。我们发现，ER应激通过NF-B激活启动细胞表达IL-1前体，并促进IL-1分泌。增强的IL-1分泌依赖于NLRP 3炎性体的激活，其机制涉及活性氧簇的形成和硫氧还蛋白相互作用蛋白的激活。化学伴侣治疗和一氧化碳的药理学应用抑制IL-1分泌响应ER应激。我们的研究结果提供了ER应激和炎症调节之间的机制联系，并表明ER应激的调节可能提供了一个治疗机会，以阻止低度慢性炎症进展为代谢综合征。
The mechanisms underlying pathophysiological states such as metabolic syndrome and obesity include endoplasmic reticulum (ER) stress and aberrant inflammatory responses. ER stress results from the accumulation of misfolded proteins during stress conditions. However, the precise mechanisms by which ER stress modulates inflammation remain incompletely understood. In this study, we hypothesized that ER stress alone could represent a sufficient signal for the modulation of inflammasome-dependent cytokine responses. We found that several ER stress-inducing chemicals and the free fatty acid palmitate can trigger IL-1 secretion in various cell types, including monocytic leukemia cells, primary macrophages and differentiated adipocytes. We show that ER stress primes cells for the expression of pro-IL-1 via NF-B activation and promotes IL-1 secretion. Enhanced IL-1 secretion depended on the activation of the NLRP3 inflammasome through a mechanism involving reactive oxygen species formation and activation of thioredoxin-interacting protein. Chemical chaperone treatment and the pharmacological application of carbon monoxide inhibited IL-1 secretion in response to ER stress. Our results provide a mechanistic link between ER stress and the regulation of inflammation, and suggest that modulation of ER stress may provide a therapeutic opportunity to block progression of low grade chronic inflammation to metabolic syndrome.