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 Szabo

Research output: Contribution to journalArticle

226 Citations (Scopus)

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 - 1998
Externally publishedYes

Fingerprint

NF-kappa B
Macrophages
melatonin
Nitric Oxide Synthase Type II
Melatonin
nitric oxide synthase
Nitric Oxide Synthase
Protein Isoforms
macrophages
Chemical activation
mice
inflammation
Inflammation
RNA Isoforms
promoter regions
prostacyclin
Hemorrhagic Shock
immunomodulators
Immunologic Factors
Epoprostenol

Keywords

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

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

Melatonin inhibits expression of the inducible isoform of nitric oxide synthase in murine macrophages : Role of inhibition of NFκB activation. / Gilad, Eli; Wong, Hector R.; Zingarelli, Basilia; Virág, László; O'Connor, Michael; Salzman, Andrew L.; Szabo, Csaba.

In: FASEB Journal, Vol. 12, No. 9, 1998, p. 685-693.

Research output: Contribution to journalArticle

Gilad, E, Wong, HR, Zingarelli, B, Virág, L, O'Connor, M, Salzman, AL & Szabo, C 1998, 'Melatonin inhibits expression of the inducible isoform of nitric oxide synthase in murine macrophages: Role of inhibition of NFκB activation', FASEB Journal, vol. 12, no. 9, pp. 685-693.
Gilad, Eli ; Wong, Hector R. ; Zingarelli, Basilia ; Virág, László ; O'Connor, Michael ; Salzman, Andrew L. ; Szabo, Csaba. / Melatonin inhibits expression of the inducible isoform of nitric oxide synthase in murine macrophages : Role of inhibition of NFκB activation. In: FASEB Journal. 1998 ; Vol. 12, No. 9. pp. 685-693.
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AU - Szabo, Csaba

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