Cytokine-specific activation of distinct MAP kinase subtype cascades in human neutrophils stimulated by cytokines and the role of MAP kinases in neutrophil activation

Abstract

We investigated activation of MAP kinase subtype cascades in human neutrophils stimulated by cytokines and the role of MAP kinases in neutrophil activation. Distinct MAP kinase subtype cascades were activated in human neutrophils stimulated by granulocyte colonystimulating factor (G-CSF), granulocyte-macrophage colonystimulating factor (GM-CSF), tumor necrosis factor-α (TNF) and interleukin-1 β (IL-1) . G-CSF selectively activated the MEK-ERK cascade, and IL-1 selectively activated the MKK 3/6-p 38 cascade, respectively. GM-CSF activated the MEK-ERK cascade strongly and the MKK 3/6-p 38 cascade weakly. TNF activated the MKK 3/6-p 38 cascade strongly and the MEK-ERK cascade weakly. The potency of these cytokines to activate the MEK-ERK cascade was GM-CSF>G-CSF=TNF, whereas that to activate the MKK 3/6-p 38 cascade was TNF>GM-CSF>IL-1. JNK was not activated by any cytokine. GM-CSF-and TNF-induced superoxide release and adherence were inhibited by PD 98059 (MEK inhibitor) as well as SB 203580 (p 38 inhibitor) . IL-1, a selective activator of p 38 cascade, also induced superoxide release and up-regulation of CD 11 b and CD 15, and both responses were inhibited by SB 203580. The results show that (a) G-CSF, GM-CSF, TNF and IL-1 activated the distinct MAP kinase subtype cascade in human neutrophils; (b) activation of ERK and p 38 is involved in superoxide release and adherence induced by cytokines.