Aspirin-mediated COX-2 transcript stabilization via sustained p38 activation in human intestinal myofibroblasts.

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Mifflin RC, Saada JI, Di Mari JF, Valentich JD, Adegboyega PA, Powell DW

Aspirin-mediated COX-2 transcript stabilization via sustained p38 activation in human intestinal myofibroblasts.

Mol Pharmacol. 2004 Feb;65(2):470-8.

PubMed ID

14742690 [ View in PubMed

]

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-1alpha (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-1beta, IL-6, groalpha, and TNFalpha) that are likewise regulated at the level of message stability via p38 activation.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Aminosalicylic acid	Prostaglandin G/H synthase 2	Protein	Humans	Unknown	Inhibitor	Details
Mesalazine	Prostaglandin G/H synthase 2	Protein	Humans	Yes	Inhibitor	Details
Sulfasalazine	Prostaglandin G/H synthase 2	Protein	Humans	Yes	Inhibitor	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Acetylsalicylic acid	Approved Vet Approved	PTGS2	5743	upregulated	Aspirin results in increased expression of PTGS2 mRNA	1q31.1
Salicylic acid	Approved Investigational Vet Approved	PTGS2	5743	upregulated	Sodium Salicylate results in increased expression of PTGS2 mRNA	1q31.1