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 language | English |
|---|---|
| Pages (from-to) | 78-87 |
| Number of pages | 10 |
| Journal | Journal of Pineal Research |
| Volume | 44 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jan 2008 |
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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 journal › Article
}
TY - JOUR
T1 - Signal transduction pathways involved in protective effects of melatonin in C6 glioma cells
AU - Esposito, Emanuela
AU - Iacono, Anna
AU - Muià, Carmelo
AU - Crisafulli, Concetta
AU - Mattace Raso, Giuseppina
AU - Bramanti, Placido
AU - Meli, Rosaria
AU - Cuzzocrea, Salvatore
PY - 2008/1
Y1 - 2008/1
N2 - 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.
AB - 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.
KW - COX-2
KW - Glioma cell line
KW - iNOS
KW - Melatonin
KW - NF-κB pathway
UR - http://www.scopus.com/inward/record.url?scp=36849059228&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=36849059228&partnerID=8YFLogxK
U2 - 10.1111/j.1600-079X.2007.00492.x
DO - 10.1111/j.1600-079X.2007.00492.x
M3 - Article
C2 - 18078452
AN - SCOPUS:36849059228
VL - 44
SP - 78
EP - 87
JO - Journal of Pineal Research
JF - Journal of Pineal Research
SN - 0742-3098
IS - 1
ER -