Aspirin-Mediated COX-2 Transcript Stabilization via Sustained p38 Activation in Human Intestinal Myofibroblasts

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

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Acetylsalicylic acid (aspirin) is a cyclooxygenase (COX) inhibitor, yet some of its therapeutic effects are thought to derive from mechanisms unrelated to prostaglandin synthesis inhibition. In human intestinal myofibroblasts, aspirin, at therapeutic doses, had the unexpected effect of inducing prolonged COX-2 expression. This induction was especially pronounced when cells were treated with interleukin-1α (IL-1) plus aspirin for 24 h. Sodium salicylate, a poor COX inhibitor, likewise enhanced IL-1-mediated COX-2 gene expression whereas 5-aminosalicylic acid (5-ASA) or indomethacin had no effect. The COX-2 transcriptional rate, measured by nuclear runoff analysis and heterogeneous nuclear RNA reverse transcription-polymerase chain reaction, was only modestly elevated by aspirin treatment. In contrast, aspirin treatment dramatically stabilized the COX-2 message. The COX-2 mRNA half-life in IL-1 treated cells was 1 h and was increased in excess of 5 h in IL-1 + aspirin-treated cells. Phosphorylation of p38 MAPK was enhanced in aspirin-treated cells (but not in cells treated with 5-ASA or indomethacin) for up to 24 h after treatment. Inhibition of p38 activity negated aspirin-mediated COX-2 mRNA stabilization and the resultant increase in COX-2 mRNA and protein levels. The modest transcriptional response seen in aspirin treated cells was also abolished by p38 inhibition. We conclude that aspirin enhances COX-2 expression via sustained activation of p38, which results in prolonged stabilization of the COX-2 message and a slightly elevated transcription rate. Aspirin also enhanced steady-state mRNA levels of other IL-1 modulated genes (IL-1β, IL-6, groα, and TNFα) that are likewise regulated at the level of message stability via p38 activation.

Original languageEnglish (US)
Pages (from-to)470-478
Number of pages9
JournalMolecular pharmacology
Volume65
Issue number2
DOIs
StatePublished - Feb 2004

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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