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.
Mifflin
Randy C
RC
Department of Internal Medicine, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA.
Saada
Jamal I
JI
Di Mari
John F
JF
Adegboyega
Patrick A
PA
Valentich
John D
JD
Powell
Don W
DW
D002460:Cell Line; D003092:Colitis / Q000276:immunology / Q000378:metabolism; D003106:Colon / Q000166:cytology* / Q000201:enzymology; D051546:Cyclooxygenase 2; D005347:Fibroblasts / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000166:cytology / Q000201:enzymology; D007527:Isoenzymes / Q000235:genetics*; D008565:Membrane Proteins; D008648:Mesoderm / Q000166:cytology / Q000201:enzymology; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D017154:Stromal Cells / Q000166:cytology / Q000201:enzymology; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D011493:Protein Kinase C; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases