Novel mechanism of cytokine-induced disruption of epithelial barriers: Janus kinase and protein kinase D-dependent downregulation of junction protein expression.
Novel mechanism of cytokine-induced disruption of epithelial barriers: Janus kinase and protein kinase D-dependent downregulation of junction protein expression.
复制标题
DOI：
10.4161/tisb.25231
复制
发表时间：
2013-10-01
期刊：
影响因子：
3.1
通讯作者：
Ivanov AI
中科院分区：
文献类型：
--
作者：
Naydenov NG;Baranwal S;Khan S;Feygin A;Gupta P;Ivanov AI
胰管上皮在胰酶进入消化系统的生理分泌中起着关键作用。胰管屏障特性的丧失可能导致胰腺炎的发生和胰腺肿瘤的转移。促炎细胞因子是胰腺炎症和肿瘤进展的重要介质；然而，它们对导管上皮的完整性和屏障特性的影响以前还没有被解决。在本研究中，我们研究了细胞因子诱导的胰腺上皮紧密连接(TJs)和黏附连接(AJs)分解的机制。HPAF-II人胰腺上皮细胞单层暴露于干扰素γ破坏了顶端连接的完整性和功能，表现为上皮通透性增加和AJ和TJ蛋白的胞浆易位。肿瘤坏死因子α可增强干扰素γ对胰腺上皮细胞连接的影响。细胞因子引起的上皮通透性增加和AJ/TJ分解可被Janus激酶(JAK)和蛋白激酶D(PKD)的药理抑制所减弱。在干扰素γ/肿瘤坏死因子α处理的HPAF-II细胞中，伴随着JAK和PKD依赖的AJ(E-钙粘蛋白，p120连环蛋白)和TJ(阻塞素，ZO-1)蛋白表达的减少。E-钙粘蛋白或p120连环蛋白的缺失概括了细胞因子对HPAF-II细胞通透性和连接的影响。我们的数据表明，促炎细胞因子通过下调AJs和TJs的关键结构成分的表达来破坏胰腺上皮屏障。这一机制可能在胰腺炎性损伤和肿瘤发生中起重要作用。
The ductal epithelium plays a key role in physiological secretion of pancreatic enzymes into the digestive system. Loss of barrier properties of the pancreatic duct may contribute to the development of pancreatitis and metastatic dissemination of pancreatic tumors. Proinflammatory cytokines are essential mediators of pancreatic inflammation and tumor progression; however, their effects on the integrity and barrier properties of the ductal epithelium have not been previously addressed. In the present study, we investigate mechanisms of cytokine-induced disassembly of tight junctions (TJs) and adherens junctions (AJs) in a model pancreatic epithelium. Exposure of HPAF-II human pancreatic epithelial cell monolayers to interferon (IFN)γ disrupted integrity and function of apical junctions as manifested by increased epithelial permeability and cytosolic translocation of AJ and TJ proteins. Tumor necrosis factor (TNF)α potentiated the effects of IFNγ on pancreatic epithelial junctions. The cytokine-induced increase in epithelial permeability and AJ/TJ disassembly was attenuated by pharmacological inhibition of Janus kinase (JAK) and protein kinase D (PKD). Loss of apical junctions in IFNγ/TNFα-treated HPAF-II cells was accompanied by JAK and PKD dependent decrease in expression of AJ (E-cadherin, p120 catenin) and TJ (occludin, ZO-1) proteins. Depletion of E-cadherin or p120 catenin recapitulated the effects of cytokines on HPAF-II cell permeability and junctions. Our data suggests that proinflammatory cytokines disrupt pancreatic epithelial barrier via expressional downregulation of key structural components of AJs and TJs. This mechanism is likely to be important for pancreatic inflammatory injury and tumorigenesis.