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

Randy C. Mifflin, Jamal I. Saada, John F. Di Mari, Patrick A. Adegboyega, John D. Valentich, Don W. Powell

Research output: Contribution to journalArticle

104 Scopus citations

Abstract

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-1α 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-κB (NF-κB), 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-κB 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-κB, 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.

Original languageEnglish (US)
Pages (from-to)C824-C834
JournalAmerican Journal of Physiology - Cell Physiology
Volume282
Issue number4 51-4
StatePublished - Jul 2 2002

Keywords

  • Eicosanoids
  • Epithelial-mesenchymal interactions
  • Intestinal carcinogenesis
  • Intestinal inflammation
  • Prostaglandins
  • Stromal cells

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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    Mifflin, R. C., Saada, J. I., Di Mari, J. F., Adegboyega, P. A., Valentich, J. D., & Powell, D. W. (2002). Regulation of COX-2 expression in human intestinal myofibroblasts: Mechanisms of IL-1-mediated induction. American Journal of Physiology - Cell Physiology, 282(4 51-4), C824-C834.