Cyclooxygenase-2 is required for activated pancreatic stellate cells to respond to proinflammatory cytokines
Cyclooxygenase-2 is required for activated pancreatic stellate cells to respond to proinflammatory cytokines
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DOI：
10.1152/ajpcell.00030.2006
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发表时间：
2007-01-01
影响因子：
5.5
通讯作者：
Sugano, Kentaro
中科院分区：
文献类型：
--
作者：
Aoki, Hiroyoshi;Ohnishi, Hirohide;Sugano, Kentaro
活化的胰腺星状细胞需要环氧合酶-2来响应促炎细胞因子。美国生理学杂志细胞生理学292：C259-C268，2007年。首次发表于2006年7月12日; doi：10.1152/ajpcell.00030.2006。环氧合酶-2（考克斯-2）介导多种炎症反应，并在慢性胰腺炎患者的胰腺组织中表达。为了研究考克斯-2在慢性胰腺炎中的作用，我们研究了其参与调节胰腺星状细胞（PSC）的功能，使用分离的大鼠PSC。考克斯-2在培养激活的PSC中表达，但在新鲜分离的静止PSC中不表达。TGF-β 1、IL-β和IL-6增强了活化PSC中的考克斯-2表达，同时增加了PSC活化参数α-平滑肌肌动蛋白（α-SMA）的表达。考克斯-2抑制剂NS-398阻断新鲜分离的静止PSC的培养活化。NS-398还抑制活化PSC中TGF-β 1、IL-1 β和IL-6对α-SMA表达的增强。这些数据表明，考克斯-2是启动和促进PSC活化所必需的。我们进一步研究了细胞因子增强PSC中考克斯-2表达的机制。腺病毒介导的显性负性Smad 2/3表达抑制了活化PSC中TGF-β 1介导的考克斯-2、α-SMA和胶原-1表达的增加。此外，显性负性Smad 2/3表达减弱了IL-1 β和IL-6增强的考克斯-2和α-SMA的表达。抗TGF-β中和抗体还减弱了IL-1 β和IL-6引起的考克斯- 2和α-SMA表达的增加。IL-6以及IL-1 β增强PSC的TGF-β 1分泌。这些数据表明，Smad 2/3依赖性途径在TGF-β 1、IL-1 β和IL-6诱导考克斯-2中起着重要作用。此外，IL-1 β和IL- 6通过增加PSC分泌TGF-β 1间接通过Smad 2/3依赖性途径增强考克斯- 2表达来促进PSC活化。
Cyclooxygenase-2 is required for activated pancreatic stellate cells to respond to proinflammatory cytokines. Am J Physiol Cell Physiol 292: C259-C268, 2007. First published July 12, 2006; doi:10.1152/ajpcell.00030.2006.-Cyclooxygenase-2 (COX-2) mediates various inflammatory responses and is expressed in pancreatic tissue from patients with chronic pancreatitis. To examine the role of COX-2 in chronic pancreatitis, we investigated its participation in regulating functions of pancreatic stellate cells (PSCs), using isolated rat PSCs. COX-2 was expressed in culture-activated PSCs but not in freshly isolated quiescent PSCs. TGF-beta 1, IL-beta, and IL-6 enhanced COX-2 expression in activated PSCs, concomitantly increasing the expression of alpha-smooth muscle actin (alpha-SMA), a parameter of PSC activation. The COX-2 inhibitor NS-398 blocked culture activation of freshly isolated quiescent PSCs. NS-398 also inhibited the enhancement of alpha-SMA expression by TGF-beta 1, IL-1 beta, and IL-6 in activated PSCs. These data indicate that COX-2 is required for the initiation and promotion of PSC activation. We further investigated the mechanism by which cytokines enhance COX-2 expression in PSCs. Adenovirus-mediated expression of dominant negative Smad2/3 inhibited the increase in expression of COX-2, alpha-SMA, and collagen-1 mediated by TGF-beta 1 in activated PSCs. Moreover, dominant negative Smad2/3 expression attenuated the expression of COX-2 and alpha-SMA enhanced by IL-1 beta and IL-6. Anti-TGF-beta neutralizing antibody also attenuated the increase in COX- 2 and alpha-SMA expression caused by IL-1 beta and IL-6. IL-6 as well as IL-1 beta enhanced TGF-beta 1 secretion from PSCs. These data indicate that Smad2/3-dependent pathway plays a central role in COX-2 induction by TGF-beta 1, IL-1 beta , and IL-6. Furthermore, IL-1 beta and IL- 6 promote PSC activation by enhancing COX- 2 expression indirectly through Smad2/3-dependent pathway by increasing TGF-beta 1 secretion from PSCs.