Regulation of COX-2 expression in human intestinal myofibroblasts: mechanisms of IL-1-mediated induction
Regulation of COX-2 expression in human intestinal myofibroblasts: mechanisms of IL-1-mediated induction
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DOI：
10.1152/ajpcell.00388.2001
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发表时间：
2002-04-01
影响因子：
5.5
通讯作者：
Powell, DW
中科院分区：
文献类型：
--
作者：
Mifflin, RC;Saada, JI;Powell, DW
在急性和慢性肠道炎症中，粘膜白细胞介素-1 （IL-1）水平升高是常见的，IL-1中和可以减轻炎症的严重程度。IL-1的一个主要作用是通过诱导环氧化酶-2 （COX-2）增加类二十烷酸介质的释放。急性和慢性肠道炎症中cox -2来源的前列腺素合成的一个位点是肠肌成纤维细胞。COX-2在结肠肿瘤细胞中也有表达。因此，了解COX-2在人肠肌成纤维细胞中的表达调控是很重要的。作为实现这一目标的第一步，我们已经在培养的人肠肌成纤维细胞中表征了诱导COX-2表达的il -1 α信号通路。IL-1处理导致COX-2基因表达的显著转录诱导。核因子- kappab （NF-kappaB）、细胞外信号调节蛋白激酶（ERK）、p38和蛋白激酶C （PKC）信号通路的激活是优化COX-2诱导的必要条件。与其他细胞类型（包括其他肌成纤维细胞，如肾系膜细胞）发生的情况相反，PKC抑制并不能阻止il -1诱导的NF-kappaB或丝裂原激活的蛋白激酶/应激激活的蛋白激酶激活，这表明PKC异构体在这一过程中发挥了新的作用。PKC、NF-kappaB、ERK-1/2和可能的c-Jun nh2末端激酶激活的刺激作用在转录水平上发挥作用，而p38激活导致COX-2信息的稳定性增加。我们得出结论，在肠肌成纤维细胞中，il -1介导的COX-2表达诱导是一个复杂的过程，需要多个信号通路的输入。每个平行通路都以相对自主的方式起作用，其作用的总和最终导致COX-2转录和信息稳定性的急剧增加。
Elevated mucosal interleukin-1 (IL-1) levels are frequently seen during acute and chronic intestinal inflammation, and IL-1 neutralization lessens the severity of inflammation. One major effect of IL-1 is the increased release of eicosanoid mediators via induction of cyclooxygenase-2 (COX-2). One site of COX-2-derived prostaglandin synthesis during acute and chronic intestinal inflammation is the intestinal myofibroblast. COX-2 expression has also been documented in these cells in colonic neoplasms. Thus an understanding of the regulation of COX-2 expression in human intestinal myofibroblasts is important. As an initial step toward this goal we have characterized IL-1alpha signaling pathways that induce COX-2 expression in cultured human intestinal myofibroblasts. IL-1 treatment resulted in a dramatic transcriptional induction of COX-2 gene expression. Activation of nuclear factor-kappaB (NF-kappaB), extracellular signal-regulated protein kinase (ERK), p38, and protein kinase C (PKC) signaling pathways was each necessary for optimal COX-2 induction. In contrast to what occurs in other cell types, including other myofibroblasts such as renal mesangial cells, PKC inhibition did not prevent IL-1-induced NF-kappaB or mitogen activated protein kinase/ stress-activated protein kinase activation, suggesting a novel role for PKC isoforms during this process. The stimulatory effects of PKC, NF-kappaB, ERK-1/2, and presumably c-Jun NH2-terminal kinase activation were exerted at the transcriptional level, whereas p38 activation resulted in increased stability of the COX-2 message. We conclude that, in intestinal myofibroblasts, IL-1-mediated induction of COX-2 expression is a complex process that requires input from multiple signaling pathways. Each parallel pathway acts in relative autonomy, the sum of their actions culminating in a dramatic increase in COX-2 transcription and message stability.