Signal transduction pathways involved in protective effects of melatonin in C6 glioma cells

Emanuela Esposito, Anna Iacono, Carmelo Muià, Concetta Crisafulli, Giuseppina Mattace Raso, Placido Bramanti, Rosaria Meli, Salvatore Cuzzocrea

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Melatonin (N-acetyl-5-methoxytryptamine), an indole hormone, is the chief secretory product of the pineal gland and is an efficient free radical scavenger and antioxidant, both in vitro and in vivo. The role of melatonin as an immunomodulator is, in some cases, contradictory. Although melatonin is reported to influence a variety of inflammatory and immune responses, evidence supporting its effects on important glioma cells-derived mediators is incomplete. We studied, in rat glioma cell line (C6), the role of melatonin (100 μm-1 mm) in the regulation of the expression of nitric oxide synthase (NOS) caused by incubation with lipopolysaccharide (LPS)/interferon (IFN)-γ (1 μg/mL and 100 U/mL, respectively) and defined the mode of melatonin's action. Treatment with LPS/IFN-γ for 24 hr elicited the induction of inducible (iNOS) activity as determined by nitrite and nitrate (NOx) accumulation in the culture medium. Preincubation with melatonin abrogated the mixed cytokines-mediated induction of iNOS. The effect of melatonin was concentration-dependent. Moreover, Western blot analysis showed that melatonin inhibited LPS/IFN-γ-induced expression of COX-2 protein, but not that of constitutive cyclooxygenase. Inhibition of iNOS and COX-2 expression was associated with inhibition of activation of the transcription factor nuclear factor kappa B (NF-κB). The ability of melatonin to inhibit NF-κB activation was further confirmed by studies on the degradation of the inhibitor of NF-κB, IκB-α. Increased production of lipid peroxidation products using thiobarbituric acid assay were found in cellular contents from activated cultures. Lipid peroxidation was decreased by melatonin treatment in a concentration-dependent manner. Moreover, several genes having roles in heat-shock response were downregulated in melatonin-treated cells, such as 70 proteins, reflecting the reduced oxidative stress in these cells. The mechanisms underlying in vitro the neuroprotective properties of melatonin involve modulation of transcription factors and consequent altered gene expression, resulting in downregulation of inflammation.

Original languageEnglish
Pages (from-to)78-87
Number of pages10
JournalJournal of Pineal Research
Volume44
Issue number1
DOIs
Publication statusPublished - Jan 2008

Fingerprint

Melatonin
Glioma
Signal Transduction
NF-kappa B
Interferons
Lipopolysaccharides
Lipid Peroxidation
Transcription Factors
Down-Regulation
5-Methoxytryptamine
Heat-Shock Response
Free Radical Scavengers
Pineal Gland
Immunologic Factors
Prostaglandin-Endoperoxide Synthases
Nitrites
Nitric Oxide Synthase
Nitrates
Culture Media
Proteins

Keywords

  • COX-2
  • Glioma cell line
  • iNOS
  • Melatonin
  • NF-κB pathway

ASJC Scopus subject areas

  • Endocrinology

Cite this

Signal transduction pathways involved in protective effects of melatonin in C6 glioma cells. / Esposito, Emanuela; Iacono, Anna; Muià, Carmelo; Crisafulli, Concetta; Mattace Raso, Giuseppina; Bramanti, Placido; Meli, Rosaria; Cuzzocrea, Salvatore.

In: Journal of Pineal Research, Vol. 44, No. 1, 01.2008, p. 78-87.

Research output: Contribution to journalArticle

Esposito, E, Iacono, A, Muià, C, Crisafulli, C, Mattace Raso, G, Bramanti, P, Meli, R & Cuzzocrea, S 2008, 'Signal transduction pathways involved in protective effects of melatonin in C6 glioma cells', Journal of Pineal Research, vol. 44, no. 1, pp. 78-87. https://doi.org/10.1111/j.1600-079X.2007.00492.x
Esposito, Emanuela ; Iacono, Anna ; Muià, Carmelo ; Crisafulli, Concetta ; Mattace Raso, Giuseppina ; Bramanti, Placido ; Meli, Rosaria ; Cuzzocrea, Salvatore. / Signal transduction pathways involved in protective effects of melatonin in C6 glioma cells. In: Journal of Pineal Research. 2008 ; Vol. 44, No. 1. pp. 78-87.
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