5-aminosalicylic acid inhibits iNOS transcription in human intestinal epithelial cells.

M. Kennedy, L. Wilson, Csaba Szabo, A. L. Salzman

Research output: Contribution to journalArticle

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Abstract

The mechanism by which 5-aminosalicylic acid (5-ASA) reduces mucosal injury in colitis is undefined. In murine cells, 5-ASA modulates the expression of the inducible nitric oxide (NO) synthase, a potential mediator of colitic injury, but its effect on the human isoform is unknown. Given the lack of conserved regulation of iNOS expression in rodent and human systems, we sought to test the effect of 5-ASA on the expression of human iNOS in cultured enterocytes. Transformed human intestinal epithelial cells, DLD-1 and Caco-2BBe, were stimulated by IL-1beta and IFN-gamma and analyzed for iNOS upregulation and NO production in the presence of various aminosalicylates. 5-ASA, but not 4-ASA, dose-dependently inhibited NO production by both cell lines [IC50 (mM) DLD-1 =4.5, Caco-2BBe =2. 5]. 5-ASA also inhibited the expression of iNOS protein and mRNA and blocked cytokine-induced transcriptional upregulation of the iNOS gene. 5-ASA (1-5 mM) had no effect on cytokine-induced nuclear translocation of NF-kappaB or expression of IRF-1, transactivating factors which regulates the human iNOS enhancer. We conclude that 5-ASA inhibits iNOS expression and NO production at therapeutically relevant concentrations. The inhibition occurs at the level of transcriptional activation and is independent of IRF-1 and NF-kappaB. Since NO is an important final effector of mucosal injury in inflammatory bowel disease, these findings may have implications for the clinical efficacy of 5-ASA.

Original languageEnglish (US)
Pages (from-to)437-443
Number of pages7
JournalInternational Journal of Molecular Medicine
Volume4
Issue number4
StatePublished - Oct 1999
Externally publishedYes

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Mesalamine
Epithelial Cells
Nitric Oxide
NF-kappa B
Wounds and Injuries
Up-Regulation
Cytokines
Enterocytes
Nitric Oxide Synthase Type II
Colitis
Inflammatory Bowel Diseases
Transcriptional Activation
Inhibitory Concentration 50
Rodentia
Protein Isoforms
Cell Line
Messenger RNA

ASJC Scopus subject areas

  • Genetics

Cite this

5-aminosalicylic acid inhibits iNOS transcription in human intestinal epithelial cells. / Kennedy, M.; Wilson, L.; Szabo, Csaba; Salzman, A. L.

In: International Journal of Molecular Medicine, Vol. 4, No. 4, 10.1999, p. 437-443.

Research output: Contribution to journalArticle

Kennedy, M. ; Wilson, L. ; Szabo, Csaba ; Salzman, A. L. / 5-aminosalicylic acid inhibits iNOS transcription in human intestinal epithelial cells. In: International Journal of Molecular Medicine. 1999 ; Vol. 4, No. 4. pp. 437-443.
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