Both Erk and p38 kinases are necessary for cytokine gene transcription

A critical feature of sepsis-induced acute lung injury is the release of cy tokines from endotoxin (LPS)stimulated alveolar macrophages (AM). LPS is al so known to activate various members of the mitogen-activated protein kinas e (MAPK) family in other types of cells. In this study, we evaluated whethe r multiple members of the MAPK family regulate cytokine gene expression in LPS-stimulated AM. We found that LPS activates both the extracellular signa l-regulated kinase (Erk) and p38 kinases, and that this activation is augme nted when the cells are cultured in serum. Inhibition of either the Erk (wi th PD98059) or p38 (with SB203580) kinase pathway resulted in only a partia l reduction in cytokine (interleukin-6 and tumor necrosis factor) messenger RNA accumulation and cytokine release, whereas inhibition of both pathways simultaneously resulted in a decrease in cytokine gene expression to near- control levels. Nuclear run-on assays showed that the effect of these MAPK pathways on LPS-induced expression of the cytokine genes was attributable, at least in part, to regulation of gene transcription. These findings sugge st that activation of both the Erk and p38 kinase pathways is necessary for optimal cytokine gene expression in LPS-stimulated human AM, and that the MAPK pathways play a critical role in the inflammatory response that occurs in sepsis-induced acute lung injury.