Thrombin and PAR-1 activating peptide increase iNOS expression in cytokine-stimulated C6 glioma cells

Thrombin (THR) plays a key role in the brain under physiological and pathological conditions. Several of the biological activities of thrombin have been shown to be mainly driven through activation of protease-activated receptor-1 (PAR-1)-type thrombin receptor. Here we have studied the effect of TH...

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Published in:Journal of neurochemistry 2001-11, Vol.79 (3), p.556-563
Main Authors: Meli, R, Raso, G M, Cicala, C, Esposito, E, Fiorino, F, Cirino, G
Format: Article
Language:English
Subjects:
Animals
Astrocytes - cytology
Astrocytes - drug effects
Astrocytes - enzymology
Cathepsin G
Cathepsins - pharmacology
Cell Division - drug effects
Drug Synergism
Glioma
Hemostatics - pharmacology
Interferon-gamma - pharmacology
Nitric Oxide Synthase - metabolism
Nitric Oxide Synthase Type II
Nitrites - metabolism
Peptide Fragments - pharmacology
protease-activated receptor 1
Rats
Serine Endopeptidases
Thrombin - pharmacology
Tumor Cells, Cultured
Tumor Necrosis Factor-alpha - pharmacology
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Summary:Thrombin (THR) plays a key role in the brain under physiological and pathological conditions. Several of the biological activities of thrombin have been shown to be mainly driven through activation of protease-activated receptor-1 (PAR-1)-type thrombin receptor. Here we have studied the effect of THR and PAR-1-activating peptide (PAR1-AP), SFLLRN, on cytokine-induced expression of inducible nitric oxide (iNOS), a prominent marker of astroglial activation using the rat C6 glioma cells. In this cell line, THR (1-10 U/mL) and PAR1-AP (1-100 microM) induced a significant concentration-dependent increase both of IFN-gamma- (250 U/mL) or TNF-alpha- (500 U/mL) induced NO release. The observed increase of NO production was related to an enhancement of iNOS expression as measured in cell lysates prepared from different treatments by using SDS-PAGE followed by western blot analysis. The effect of THR, but not that of PAR1-AP, was significantly inhibited by hirulog(TM) (60 microg/mL), a specific and stochiometric THR inhibitor or by cathepsin-G (40 mU/mL), an inhibitor of PAR-1. In conclusion our data suggest a role for THR through activation of PAR-1 in the induction of astroglial iNOS, and further support the hypothesis that THR may function as an important pathophysiological modulator of the inflammatory response.
ISSN:0022-3042
DOI:10.1046/j.1471-4159.2001.00617.x