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

Michelle Kennedy, Lori Wilson, Csaba Szabö, Andrew L. Salzman

    Research output: Contribution to journalArticle

    25 Scopus citations

    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-I&szligl and IFN-γ and analyzed for iNOS upregulation and NO production in the presence of various aminosalicylates. 5-ASA, but not 4-ASA, dosedependently 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-κB 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-κB. 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 1 1999

    Keywords

    • 5-ASA
    • Caco-2BBe
    • DLD-1
    • Enterocyte
    • Epithelium
    • Free radical
    • IRF-1
    • Inducible nitric oxide synthase
    • Inflammatory bowel disease
    • Intestinal mucosa
    • NF-κB
    • Nitric oxide

    ASJC Scopus subject areas

    • Genetics

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