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

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 NH(2)-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.
Mesh Terms:
Cell Line, Colitis, Colon, Cyclooxygenase 2, Fibroblasts, Gene Expression Regulation, Enzymologic, Humans, Interleukin-1, Intestinal Mucosa, Isoenzymes, Membrane Proteins, Mesoderm, Mitogen-Activated Protein Kinase 8, Mitogen-Activated Protein Kinases, NF-kappa B, Prostaglandin-Endoperoxide Synthases, Protein Kinase C, RNA, Messenger, Stromal Cells, Transcriptional Activation, p38 Mitogen-Activated Protein Kinases
Am. J. Physiol., Cell Physiol.
Date: Apr. 01, 2002
Download Curated Data For This Publication
157629
Switch View:
  • Interactions 2