P38 Mitogen-Activated Protein Kinase and Extracellular Signal-Regulated Kinase Regulate Nitric Oxide Production and Inflammatory Cytokine Expression in Raw Cells

Abstract

p38 and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) signaling are thought to have critical role in lipopolysaccharide (LPS)-induced immune response but the molecular mechanism underlying the induction of these signaling are not clear. Methods: Specific inhibitors for p38, SB203580, and for ERK, PD98059 were used. Cells were stimulated by LPS with or without specific MAPK inhibitors. Results: LPS activated inducible nitric oxide synthase (iNOS), subsequent NO productions, and pro-inflammatory cytokine gene expressions (TNF-α, IL-1β, IL-6, and IL-12). Treatment of both SB203580 and PD98059 decreased LPS-induced NO productions. Concomitant decreases in the expression of iNOS mRNA and protein were detected. SB203580 and PD98059 decreased LPS-induced gene expression of IL-1β and IL-6. SB203580 increased LPS-induced expression of TNF-α and IL-12, and reactive oxygen species production, but PD98059 had no effect. Conclusion: These results indicate that both p38 and ERK pathways are involved in LPS-stimulated NO synthesis, and expression of IL-1β and IL-6. p38 signaling pathways are involved in LPS-induced TNF-α and IL-12, and reactive oxygen species plays an important role in these signaling in macrophage.