ヒト好中球ＭＡＰキナーゼサブタイプのサイトカイン（Ｇ‐ＣＳＦ，ＧＭ‐ＣＳＦ，ＴＮＦ）特異的活性化と活性酸素産生

Abstract

In order to clarify the differences of the signaling pathways utilized by G-CSF, GM-CSF and TNF, we investigated activation of MAPK subtype cascades in human neutrophils stimulated by these cytokines. G-CSF exclusively activates the MEK-ERK cascade. GM-CSF activates the MEK-ERK cascade strongly and the MKK 3/ 6-p 38 MAPK cascade weakly, whereas TNF activates the MKK 3/6-p 38 MAPK 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 MAPK cascade was TNF>GM-CSF. JNK was not tyrosine-phosphorylated by any cytokine in spite of the existence of JNK proteins in human neutrophils, whereas it was tyrosine-phosphorylated by TNF in undifferentiated and all-trans retinoic acid-differentiated HL-60 cells. Increased phosphorylation of ERK or p 38 MAPK was detected within 1-5 minutes after stimulation with each cytokine and was dependent on the concentrations of cytokines used. GM-CSF-or TNF-induced superoxide (O2-) release was inhibited by p 38 MAPK inhibitor (SB203580) in a dose-dependent manner. The results indicate that G-CSF, GM-CSF and TNF activate the overlapping but distinct MAPK subtype cascades in human neutrophils and p 38 MAPK may be involved in GM -CSF-or TNF-induced O2- release.