Selective activation of p38 mitogen-activated protein kinase cascade in human neutrophils stimulated by IL-1β

We investigated activation of mitogen-activated protein kinase (MAPK) subtype cascades in human neutrophils stimulated by IL-1 beta. IL-1 beta induced phosphorylation. and activation of p38 MAPK and phosphorylation of MAPK kinase-3/6 (MKK3/6). Maximal activation of p38 MAPK was obtained by stimulation of cells with 300 U/ml IL-1 beta for 10 min. Extracellular signal-regulated kinase (ERK) was faintly phosphorylated and c-Jun N-terminal kinase (JNK) was not phosphorylated by IL-1 beta. IL-1 beta primed neutrophils for enhanced release of superoxide (O-2(-)) stimulated by FMLP in parallel with increased phosphorylation of p38 MAPK. IL-1 beta also induced O-2(-) release and up-regulation of CD11b and CD15, and both responses were inhibited by SB203580 (p38 MAPK inhibitor), suggesting that p38 MAPK activation mediates IL-1 beta -induced O-2(-) release and up-regulation of CD11b and CD15. Combined stimulation of neutrophils, with IL-1 beta and G-CSF, a selective activator of the ERK cascade, resulted in the additive effects when the priming effect and phosphorylation of p38 MAPK and ERK were assessed. IL-1 beta induced phosphorylation of ERK and JNK as well as p38 AWK in human endothelial cells. These findings suggest that 1) in human neutrophils the MKK3/6-p38 MAPK cascade is selectively activated by IL-1 beta and activation of this cascade mediates IL-1 beta -induced O-2(-) release and up-regulation of CD11b and CD15, and 2) the lL-1R-p38 MAPK pathway and the G-CSF receptor-ERK pathway work independently for activation of neutrophils.