Abstract
BackgroundNitric oxide (NO) is an inflammatory mediator, which acts as a cytotoxic agent and modulates immune responses and inflammation. p38 mitogen-activated protein kinase (MAPK) signal transduction pathway is activated by chemical and physical stress and regulates immune responses. Previous studies have shown that p38 MAPK pathway regulates NO production induced by inflammatory stimuli. The aim of the present study was to investigate the mechanisms involved in the regulation of inducible NO synthesis by p38 MAPK pathway.Resultsp38 MAPK inhibitors SB203580 and SB220025 stimulated lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) expression and NO production in J774.2 murine macrophages. Increased iNOS mRNA expression was associated with reduced degradation of iNOS mRNA. Treatment with SB220025 increased also LPS-induced c-Jun N-terminal kinase (JNK) activity. Interestingly, JNK inhibitor SP600125 reversed the effect of SB220025 on LPS-induced iNOS mRNA expression and NO production.ConclusionThe results suggest that inhibition of p38 MAPK by SB220025 results in increased JNK activity, which leads to stabilisation of iNOS mRNA, to enhanced iNOS expression and to increased NO production.
Highlights
Nitric oxide (NO) is an inflammatory mediator, which acts as a cytotoxic agent and modulates immune responses and inflammation. p38 mitogen-activated protein kinase (MAPK) signal transduction pathway is activated by chemical and physical stress and regulates immune responses
The results suggest that inhibition of p38 MAPK increases LPS-induced Jun N-terminal kinase (JNK) activity, which leads to stabilisation of inducible nitric oxide synthase (iNOS) mRNA and increased production of NO in activated macrophages
EiFNfifgeOucStreoexf3pr3e8ssMioAnPK inhibitor SB220025 on LPS-induced Effect of p38 MAPK inhibitor SB220025 on LPSinduced iNOS expression. (A) Cells were stimulated with LPS 1 h before addition of SB220025
Summary
Nitric oxide (NO) is an inflammatory mediator, which acts as a cytotoxic agent and modulates immune responses and inflammation. p38 mitogen-activated protein kinase (MAPK) signal transduction pathway is activated by chemical and physical stress and regulates immune responses. Nitric oxide (NO) is an inflammatory mediator, which acts as a cytotoxic agent and modulates immune responses and inflammation. P38 mitogen-activated protein kinase (MAPK) signal transduction pathway is activated by chemical and physical stress and regulates immune responses. Previous studies have shown that p38 MAPK pathway regulates NO production induced by inflammatory stimuli. Nitric oxide (NO) is a highly reactive signaling molecule and inflammatory mediator, which acts as a cytotoxic agent and modulates immune responses and inflammation [1,2]. Mitogen-activated protein kinases (MAPKs) are a family of serine/threonine kinases that are part of the signal transduction pathways, which connect inflammatory and various other extracellular signals to intracellular responses e.g. gene expression [6]. 24 h after addition of LPS the nitrite concentrations were measured as marker of NO production.
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