A small molecule inhibitor of NFκB blocks ER stress and the NLRP3 inflammasome and prevents progression of pancreatitis
A small molecule inhibitor of NFκB blocks ER stress and the NLRP3 inflammasome and prevents progression of pancreatitis
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DOI：
10.1007/s00535-016-1238-5
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发表时间：
2017-03-01
影响因子：
6.3
通讯作者：
Naziruddin, Bashoo
中科院分区：
文献类型：
--
作者：
Kanak, Mazhar A.;Shahbazov, Rauf;Naziruddin, Bashoo
导致慢性胰腺炎发展的潜在分子机制仍然难以捉摸。为了解慢性胰腺炎发生发展过程中下游炎症信号的变化，并利用核因子κ B（NF kappa B）的小分子抑制剂withaferin A（WA）预防慢性胰腺炎的发生发展，采用标准和严格的雨蛙肽诱导小鼠胰腺炎模型。通过胰腺组织学和血清淀粉酶水平评估胰腺炎的严重程度。进行免疫组织化学和流式细胞术分析以观察免疫细胞浸润到胰腺中。实时荧光定量PCR和Western blot分析慢性胰腺炎发生的下游信号转导机制，结果表明，无论是预防性治疗还是治疗性治疗，WA均能显著降低蛙皮素诱导的胰腺炎的严重程度。免疫细胞浸润到胰腺和腺泡细胞死亡有效地减少WA治疗。蛙皮素处理可增加NF κ B B活化调节的促炎和促凋亡基因的表达，而WA可显著抑制这些基因的表达。持续内质网应激激活雨蛙肽管理减少。NLRP 3炎性小体激活在蛙皮素诱导的胰腺炎中被鉴定，并且这也被WA有效地阻断。人胰腺炎组织基因签名与小鼠模型相关，为NF κ B B在慢性胰腺炎发病机制中的作用提供了证据，并有力地表明WA可作为一种潜在的治疗药物来缓解某些形式的慢性胰腺炎。
The underlying molecular mechanism that leads to development of chronic pancreatitis remains elusive. The aim of this study is to understand the downstream inflammatory signaling involved in progression of chronic pancreatitis, and to use withaferin A (WA), a small molecule inhibitor of nuclear factor kappa B (NF kappa B), to prevent progression of chronic pancreatitis.Two different protocols were used to induce pancreatitis in mice: standard and stringent administration of cerulein. The severity of pancreatitis was assessed by means of pancreatic histology and serum amylase levels. Immunohistochemistry and flow-cytometric analysis was performed to visualize immune cell infiltration into the pancreas. Real-time PCR and Western blot were used to analyze the downstream signaling mechanism involved in the development of chronic pancreatitis.The severity of cerulein-induced pancreatitis was reduced significantly by WA, used as either preventive or curative treatment. Immune cell infiltration into the pancreas and acinar cell death were efficiently reduced by WA treatment. Expression of proinflammatory and proapoptotic genes regulated by NF kappa B activation was increased by cerulein treatment, and WA suppressed these genes significantly. Sustained endoplasmic reticulum stress activation by cerulein administration was reduced. NLRP3 inflammasome activation in cerulein-induced pancreatitis was identified, and this was also potently blocked by WA. The human pancreatitis tissue gene signature correlated with the mouse model.Our data provide evidence for the role of NF kappa B in the pathogenesis of chronic pancreatitis, and strongly suggest that WA could be used as a potential therapeutic drug to alleviate some forms of chronic pancreatitis.