Roles of MAP kinases and STAT3 in proliferation and differentiation of normal human hematopoietic progenitor cells

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Distinct MAP kinase subtype cascades (MEK-ERK, MKK3/6-p38 and MKK4/7-JNK) were found to be activated in normal human hematopoietic progenitor cells (CD34^+ cells) stimulated by various cytokines (SCF, G-CSF, TPO, GM-CSF, IL-6/sIL-6R, IL-3, IL-1β, TNFα, IFNα and IFNγ) in a cytokine-specific manner. Likewise, distinct STAT molecules (STAT3, STAT5a, STAT5b and STAT1) were also tyrosine-phosphorylated by these cytokines in a cytokine-specific manner. SCF, IL-6/sIL-6R and G-CSF serine-phosphorylated STAT3 through activation of ERK and/or H7-sensitive kinase according to the stimuli used ; I. e., ERK was involved in SCF- and G-CSF-mediated phosphorylation, and H7-sensitive kinase was involved in IL-6/sIL-6R- and G-CSF-mediated phosphorylation. Serine-phosphorylation of STAT3 was also regulated by PI-3 kinase. ERK was primarily involved in proliferation of CD34^+ cells, whereas STAT3 was primarily involved in cell survival. Coordinated activation of ERK and STAT3 resulted in the synergistic effect on proliferation and survival of CD34^+ cells. MAK kinase subtypes activated by stimulation with cytokines and their roles in cell functions were altered during differentiation into mature neutrophils and were dependent on the stages of differentiation of cells. In mature neutrophils, MEK-ERK and/or MKK3/6-p38, but not MKK4/7-JNK, were activated by stimulation with various cytokines (G-CSF, GM-CSF, TNFα and IL-1β) in a cytokine-specific manner. Both pathways were involved in cytokine-induced activation of neutrophil functions such as superoxide release, adherence and up-regulation of adhesion molecules (CD11b and CD15).