Intracellular signaling mechanisms in normal human hematopoietic progenitors and mature leukocytes

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1.Regulation of actin reorganization and motility in human neutrophils by cytokines : Stimulation of neutrophils with G-CSF, GM-CSF or TNF-α resulted in actin de polymerization and morphological change. The maximum responses were detected within 20 min. We found that activation of ERK and p38 MAPK plays a critical role in actin reorganization and morphological change induced by these cytokines. G-CSF also induced random migration in neutrophils, and G-CSF-induced neutrophil migration was regulated by ERK and P13K.2.Regulation of human monocyte functions by G-CSF : Among the signaling molecules, STAT3 was selectively activated in monocytes stimulated by G-CSF. We found that G-CSF inhibited LPS-induced TNF-α production in monocytes through activation of STAT3. The immunomodulation observed in vivo by G-CSF administration may be partly ascribed to the direct effect of G-CSF on monocyte functions.3.Human neutrophil survival and cIAP2 : Human neutrophils were found to express members of the inhibitor of apoptosis (IAP) family, namely cIAP1, cIAP2 and XIAP. Among these members, cIAP2 expression was selectively up-regulated by G-CSF stimulation in vitro and in vivo. Up-regulation of cIAP2 expression was mediated by activation of the JAK2-STAT3 pathway. Increased expression of cIAP2 protein may contribute to G-CSF-mediated anti-apoptotic effect on neutrophils. In addition, we found that mature neutrophils from a patient with chronic neutrophilic leukemia exhibited remarkable over-expression of cIAP2 mRNA and prolongation of survival.4.STAT3 isoforms expressed in human neutrophils : It has been reported that STAT3γ is a major STAT3 isoform in human neutrophils. We found that, in contrast to the previous reports, STAT3α, but not STAT3γ, was primarily expressed in human neutrophils, and STAT3γ was rapidly generated from STAT3α by limited proteolysis with granule-derived serine proteases during preparation of neutrophil lysates with the conventional lysis buffer.