Document Detail


Aspirin-mediated COX-2 transcript stabilization via sustained p38 activation in human intestinal myofibroblasts.
MedLine Citation:
PMID:  14742690     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Randy C Mifflin; Jamal I Saada; John F Di Mari; John D Valentich; Patrick A Adegboyega; Don W Powell
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Molecular pharmacology     Volume:  65     ISSN:  0026-895X     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  2004 Feb 
Date Detail:
Created Date:  2004-01-26     Completed Date:  2004-03-12     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  470-8     Citation Subset:  IM    
Affiliation:
Department of Internal Medicine, Division of Gastroenterology, University of Texas Medical Branch, Galveston, Texas 77555-1058, USA. rmifflin@utmb.edu
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MeSH Terms
Descriptor/Qualifier:
Aspirin / pharmacology*
Cells, Cultured
Cyclooxygenase 2
Enzyme Activation / drug effects,  genetics
Fibroblasts / drug effects,  enzymology*
Gene Expression Regulation, Enzymologic / drug effects,  genetics
Humans
Intestines / cytology,  drug effects,  enzymology*
Isoenzymes / biosynthesis*,  genetics
Membrane Proteins
Mitogen-Activated Protein Kinases / genetics,  metabolism*
Prostaglandin-Endoperoxide Synthases / biosynthesis*,  genetics
RNA Stability / drug effects*,  genetics
Transcription, Genetic / drug effects*,  physiology
p38 Mitogen-Activated Protein Kinases
Grant Support
ID/Acronym/Agency:
DK55783/DK/NIDDK NIH HHS; DK56338/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Isoenzymes; 0/Membrane Proteins; 50-78-2/Aspirin; EC 1.14.99.1/Cyclooxygenase 2; EC 1.14.99.1/PTGS2 protein, human; EC 1.14.99.1/Prostaglandin-Endoperoxide Synthases; EC 2.7.11.24/Mitogen-Activated Protein Kinases; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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