Evidence that N-acetylcysteine inhibits TNF-alpha-induced cerebrovascular endothelin-1 upregulation via inhibition of mitogen- and stress-activated protein kinase
| Autor: | Stephan Christen, Manuela Frese-Schaper, Matthias D. Sury, Sidney Shaw, Ingolf E. Blasig, Fabienne T. Schulthess, Martin G. Täuber, Miranda K. Mühlemann |
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| Rok vydání: | 2005 |
| Předmět: |
MAPK/ERK pathway
medicine.drug_class MAP Kinase Signaling System p38 mitogen-activated protein kinases Nitric Oxide Synthase Type II Biology Biochemistry Ribosomal Protein S6 Kinases 90-kDa Cell Line Downregulation and upregulation Physiology (medical) medicine Animals Kinase activity Enzyme Inhibitors Phosphorylation Protein kinase A Nitrites Nitrates Endothelin-1 Tumor Necrosis Factor-alpha NF-kappa B Brain Free Radical Scavengers Protein kinase inhibitor Molecular biology Endothelin 1 Acetylcysteine Rats Up-Regulation Nitric oxide synthase Protein Transport biology.protein Endothelium Vascular |
| Zdroj: | Free radical biologymedicine. 41(9) |
| ISSN: | 0891-5849 |
| Popis: | N-acetylcysteine (NAC) is neuroprotective in animal models of acute brain injury such as caused by bacterial meningitis. However, the mechanism(s) by which NAC exerts neuroprotection is unclear. Gene expression of endothelin-1 (ET-1), which contributes to cerebral blood flow decline in acute brain injury, is partially regulated by reactive oxygen species, and thus a potential target of NAC. We therefore examined the effect of NAC on tumor necrosis factor (TNF)-alpha-induced ET-1 production in cerebrovascular endothelial cells. NAC dose dependently inhibited TNF-alpha-induced preproET-1 mRNA upregulation and ET-1 protein secretion, while upregulation of inducible nitric oxide synthase (iNOS) was unaffected. Intriguingly, NAC had no effect on the initial activation (i.e., IkappaB degradation, nuclear p65 translocation, and Ser536 phosphorylation) of NF-kappaB by TNF-alpha. However, transient inhibition of NF-kappaB DNA binding suggested that NAC may inhibit ET-1 upregulation by inhibiting (a) parallel pathway(s) necessary for full transcriptional activation of NF-kappaB-mediated ET-1 gene expression. Similar to NAC, the MEK1/2 inhibitor U0126, the p38 inhibitor SB203580, and the protein kinase inhibitor H-89 selectively inhibited ET-1 upregulation without affecting nuclear p65 translocation, suggesting that NAC inhibits ET-1 upregulation via inhibition of mitogen- and stress-activated protein kinase (MSK). Supporting this notion, cotreatment with NAC inhibited the TNF-alpha-induced rise in MSK1 and MSK2 kinase activity, while siRNA knock-down experiments showed that MSK2 is the predominant isoform involved in TNF-alpha-induced ET-1 upregulation. |
| Databáze: | OpenAIRE |
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