Celastrol inhibits production of nitric oxide and proinflammatory cytokines through MAPK signal transduction and NF-kappaB in LPS-stimulated BV-2 microglial cells

Excessive production of nitric oxide (NO) and proinflammatory cytokines from activated microglia play an important role in human neurodegenerative disorders. Here, we investigated whether celastrol, which has been used as a potent anti-inflammatory and anti-oxidative agent in Chinese medicine, atten...

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Bibliographic Details
Published in:Experimental & molecular medicine 2007-12, Vol.39 (6), p.715
Main Authors: Jung, Hyo Won, Chung, Yoo Sun, Kim, Yoon Seong, Park, Yong-Ki
Format: Article
Language:English
Subjects:
Animals
Cell Line
Cytokines - biosynthesis
Cytokines - drug effects
Gene Expression Regulation, Enzymologic - drug effects
Gene Expression Regulation, Enzymologic - immunology
Inflammation - immunology
Inflammation Mediators - immunology
Mice
Microglia - drug effects
Microglia - immunology
Mitogen-Activated Protein Kinases - physiology
NF-kappa B - metabolism
NF-kappa B - physiology
Nitric Oxide - metabolism
Nitric Oxide Synthase Type II - biosynthesis
Nitric Oxide Synthase Type II - drug effects
RNA, Messenger - analysis
Signal Transduction - drug effects
Signal Transduction - physiology
Transcription, Genetic - drug effects
Transcription, Genetic - immunology
Triterpenes - pharmacology
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Summary:Excessive production of nitric oxide (NO) and proinflammatory cytokines from activated microglia play an important role in human neurodegenerative disorders. Here, we investigated whether celastrol, which has been used as a potent anti-inflammatory and anti-oxidative agent in Chinese medicine, attenuates excessive production of NO and proinflammatory cytokines such as TNF-alpha and IL-1betal in LPS-stimulated BV-2 cells, a mouse microglial cell line. We report here that the LPS-elicited excessive production of NO, TNF-alpha, and IL-1beta in BV-2 cells was largely inhibited in the presence of celastrol, and the attenuation of inducible iNOS and these cytokines resulted from the reduced expression of mRNAs of iNOS and these cytokines, respectively. The molecular mechanisms that underlie celastrol-mediated attenuation were the inhibition of LPS-induced phosphorylation of MAPK/ERK1/2 and the DNA binding activity of NF-kappaB in BV-2 cells. The results indicate that celastrol effectively attenuated NO and proinflammatory cytokine production via the inhibition of ERK1/2 phosphorylation and NF-kappaB activation in LPS-activated microglia. Thus, celastrol may be an effective therapeutic candidate for use in the treatment of neurodegenerative human brain disorders.
ISSN:1226-3613