Salicylate inhibition of extracellular signal-regulated kinases and inducible nitric oxide synthase.
The expression of inducible nitric oxide synthase (iNOS) is a characteristic response to inflammation and can be inhibited with sodium salicylate. We used the cytokine-induced iNOS induction in cardiac fibroblasts as a model system in which to test the hypothesis that effects on mitogen-activated protein kinases (MAPKs) may explain the mechanism by which salicylate exerts its anti-inflammatory effects. Tumor necrosis factor-alpha (TNF-alpha) alone can induce extracellular signal-regulated kinase (ERK), p38 MAPK, and c-Jun N-terminal kinase activity in a rapid and transient manner, whereas interferon-gamma (IFN-gamma) can induce only ERK. The inhibition of either the ERK pathway or p38 MAPK activity with selective inhibitors blocked cytokine-induced iNOS protein and nitrite production. Salicylate treatment inhibited iNOS expression induced by TNF-alpha and IFN-gamma and attenuated the phosphorylation of ERK by TNF-alpha and IFN-gamma either alone or in combination. Salicylate had no obvious effect on the activation of p38 MAPK or c-Jun N-terminal kinase. The results showed that salicylate inhibited the phosphorylation of ERK and iNOS expression induced by cytokines in a dose-dependent manner and suggested that salicylate exerts its anti-inflammatory action in part through inhibition of the ERK pathway and iNOS induction.
Wang
Z
Z
Whitaker Cardiovascular Institute and Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.
Brecher
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D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015153:Blotting, Western; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D007371:Interferon-gamma / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009206:Myocardium / Q000166:cytology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012980:Sodium Salicylate / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D012980:Sodium Salicylate