Melatonin inhibits expression of the inducible isoform of nitric oxide synthase in murine macrophages: Role of inhibition of NFκB activation

Eli Gilad, Hector R. Wong, Basilia Zingarelli, László Virág, Michael O'Connor, Andrew L. Salzman, Csaba Szabó

    Research output: Contribution to journalArticle

    230 Scopus citations

    Abstract

    The role of melatonin as an immunomodulator is well established. Recent reports showed that melatonin exerts protective effects in septic and hemorrhagic shock and in inflammation. The expression of the inducible isoform of nitric oxide synthase (iNOS) makes an important contribution to the pathophysiology of shock and inflammation. We studied, in cultured murine macrophages, the role of melatonin in the regulation of the expression of iNOS and defined the mode of melatonin's action. Our results show that melatonin, at 1 μM-1 mM, decreased the production of nitrite/nitrate (the breakdown products of NO) as well as the production of 6-ketoprostaglandin F(lα) (the major stable breakdown product of prostacyclin) in macrophages stimulated with bacterial lipopolysaccharide (10 μg/ml). We observed that melatonin reduces iNOS steady-state mRNA levels and iNOS protein expression in the same concentration range (1 μM-1 mM). Melatonin, up to 10 mM, exerted only a slight direct inhibitory effect on iNOS activity. Using iNOS promoter- luciferase constructs, we found that melatonin inhibits iNOS promoter activation. Inhibition of iNOS expression was associated with inhibition of activation of the transcription factor nuclear factor kappa B (NFκB). We conclude that melatonin inhibits NO production in immunostimulated macrophages mainly by inhibiting the expression of iNOS. This is due to inhibition of iNOS transcription, in part through inhibition of NFκB activation. Inhibition of iNOS-derived NO production by melatonin may contribute to the anti-inflammatory effects of this pineal secretory product. - Gilad, E., Wong, H. R., Zingarelli, B., Virag, L., O'Connor, M., Salzman, A. L., Szabo, G. Melatonin inhibits expression of the inducible isoform of nitric oxide synthase in murine macrophages: role of inhibition of NFκB activation.

    Original languageEnglish (US)
    Pages (from-to)685-693
    Number of pages9
    JournalFASEB Journal
    Volume12
    Issue number9
    StatePublished - Jan 1 1998

    Keywords

    • Antioxidants
    • Gen expression
    • Inflammation
    • LPS
    • Mesangial cells
    • Scavengers

    ASJC Scopus subject areas

    • Biotechnology
    • Biochemistry
    • Molecular Biology
    • Genetics

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  • Cite this

    Gilad, E., Wong, H. R., Zingarelli, B., Virág, L., O'Connor, M., Salzman, A. L., & Szabó, C. (1998). Melatonin inhibits expression of the inducible isoform of nitric oxide synthase in murine macrophages: Role of inhibition of NFκB activation. FASEB Journal, 12(9), 685-693.