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Am J Physiol Cell Physiol 282: C824-C834, 2002. First published November 14, 2001; doi:10.1152/ajpcell.00388.2001
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Vol. 282, Issue 4, C824-C834, April 2002

Regulation of COX-2 expression in human intestinal myofibroblasts: mechanisms of IL-1-mediated induction

Randy C. Mifflin1, Jamal I. Saada1, John F. Di Mari1, Patrick A. Adegboyega3, John D. Valentich1, and Don W. Powell1,2

Departments of 1 Internal Medicine, 2 Physiology and Biophysics, and 3 Pathology, University of Texas Medical Branch, Galveston, Texas 77555

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-kappa B (NF-kappa B), 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-kappa B 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-kappa B, 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.

prostaglandins; eicosanoids; intestinal inflammation; intestinal carcinogenesis; stromal cells; epithelial-mesenchymal interactions


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