HETEs enhance IL-1-mediated COX-2 expression via augmentation of message stability in human colonic myofibroblasts

J. F. Di Mari, J. I. Saada, R. C. Mifflin, J. D. Valentich, D. W. Powell

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Proinflammatory cytokines and eicosanoids are central players in intestinal inflammation. IL-1, a key cytokine associated with intestinal mucosal inflammation, induces COX-2 expression in human colonic myofibroblasts (CMF) and increased prostaglandin E2 secretion is associated with inflammatory bowel disease (IBD) and colorectal cancer (CRC). We have previously demonstrated that IL-1α-induced cyclooxygenase-2 (COX-2) expression is the result of NF-κB- and ERK-mediated transcription, as well as COX-2 message stabilization, which depends on p38, MAPKAPK-2 (MK-2) and human antigen R (HuR) RNA binding protein activation. Lipoxygenase (LOX)-derived hydroxyeicosatetraenoic acids (HETEs) are elevated in IBD and colonic adenomas and "cross talk" has been observed between the COX and LOX pathways. Since COX-2 expression is primarily in CMFs in colonic adenomas, we examined the impact of LOX metabolites, particularly HETEs, on IL-1α-induced COX-2 expression in human CMFs. Although 5(S)-, 12(R)-, and 15(S)-HETEs alone had little to no effect on COX-2 expression, they enhanced IL-1-mediated COX-2 expression 3.6 ± 0.5-fold. Studies utilizing heterogeneous nuclear RNA amplification and 5,6-dichloro-β-D-ribofuranosylbenzimidazole treatment were undertaken to measure COX-2 transcription and message stabilization, respectively. We found that HETEs enhanced IL-1-induced COX-2 mRNA levels in CMF as the result of increased p38, MK-2, and HuR activity, increasing message stability greater than that observed with IL-1 alone. Thus HETEs can act synergistically with IL-1α to induce COX-2 expression in human CMFs. HETEs may play a role in both colonic inflammation and in increasing the risk of CRC in IBD independently and via induction of COX-2-mediated prostaglandin secretion.

Original languageEnglish (US)
Pages (from-to)G719-G728
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume293
Issue number4
DOIs
StatePublished - Oct 1 2007

Keywords

  • Colorectal cancer
  • Cyclooxygenases
  • Lipoxygenases
  • Prostaglandins

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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