Cathepsin B Contributes to Autophagy-related 7 (Atg7)-induced Nod-like Receptor 3 (NLRP3)-dependent Proinflammatory Response and Aggravates Lipotoxicity in Rat Insulinoma Cell Line
Cathepsin B Contributes to Autophagy-related 7 (Atg7)-induced Nod-like Receptor 3 (NLRP3)-dependent Proinflammatory Response and Aggravates Lipotoxicity in Rat Insulinoma Cell Line
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DOI：
10.1074/jbc.m113.494286
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发表时间：
2013-10-18
影响因子：
4.8
通讯作者：
Yang, SiJun
中科院分区：
文献类型：
--
作者：
Li, Shali;Du, Leilei;Yang, SiJun
背景：以往的研究表明，自噬缺陷导致炎性小体激活。结果：过度的自噬激活诱导了促炎反应。结论：我们的研究结果为自噬调控促炎细胞因子的释放机制提供了新的见解。重要性：自噬可能在T2 D的发病机制中起有害作用是一个新的发现。在细胞中发现棕榈酸酯的脂毒性导致葡萄糖刺激的胰岛素分泌受损。最近的研究表明，自噬缺陷有助于2型糖尿病的发病机制。在这里，我们报告，自噬相关的7（Atg 7）诱导过度自噬激活INS-1（823/13）细胞暴露于饱和脂肪酸。Atg 7诱导的组织蛋白酶B（CTSB）过表达导致促炎趋化因子和IL-1、单核细胞趋化蛋白-1、IL-6和TNF-α的细胞因子产生水平意外显著增加。抑制受体相互作用蛋白并不影响炎症反应，排除坏死的参与。CTSB siRNA抑制炎症反应，但不影响凋亡显着，表明CTSB是自噬和促炎反应之间的分子连接器。阻断caspase-3抑制细胞凋亡，但不影响炎症反应，表明CTSB诱导的炎症反应独立于细胞凋亡。Nod样受体3（NLRP 3）的沉默完全消除了IL-1分泌和Atg 7诱导的CTSB过表达对葡萄糖刺激的胰岛素分泌障碍的下调作用，从而将NLRP 3炎性小体鉴定为胰腺INS-1（823/13）细胞系中的自噬反应元件。结合在一起，我们的结果表明，CTSB有助于Atg 7诱导的NLRP 3依赖性促炎反应，导致脂毒性加重，独立于胰腺INS-1（823/13）细胞系的凋亡。
Background: Previous studies show that autophagy deficiency leads to inflammasome activation. Results: Excessive autophagy activation induces a proinflammatory response. Conclusion: Our findings provide new insights into the release mechanisms of proinflammatory cytokines regulated by autophagy. Significance: That autophagy may play a deleterious role in pathogenesis in T2D is a novel finding.Impairment of glucose-stimulated insulin secretion caused by the lipotoxicity of palmitate was found in -cells. Recent studies have indicated that defects in autophagy contribute to pathogenesis in type 2 diabetes. Here, we report that autophagy-related 7 (Atg7) induced excessive autophagic activation in INS-1(823/13) cells exposed to saturated fatty acids. Atg7-induced cathepsin B (CTSB) overexpression resulted in an unexpected significant increase in proinflammatory chemokine and cytokine production levels of IL-1, monocyte chemotactic protein-1, IL-6, and TNF-. Inhibition of receptor-interacting protein did not affect the inflammatory response, ruling out involvement of necrosis. CTSB siRNA suppressed the inflammatory response but did not affect apoptosis significantly, suggesting that CTSB was a molecular linker between autophagy and the proinflammatory response. Blocking caspase-3 suppressed apoptosis but did not affect the inflammatory response, suggesting that CTSB induced inflammatory effects independently of apoptosis. Silencing of Nod-like receptor 3 (NLRP3) completely abolished both IL-1 secretion and the down-regulation effects of Atg7-induced CTSB overexpression on glucose-stimulated insulin secretion impairment, thus identifying the NLRP3 inflammasome as an autophagy-responsive element in the pancreatic INS-1(823/13) cell line. Combined together, our results indicate that CTSB contributed to the Atg7-induced NLRP3-dependent proinflammatory response, resulting in aggravation of lipotoxicity, independently of apoptosis in the pancreatic INS-1(823/13) cell line.