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RECEPTORS AND SIGNAL TRANSDUCTION

Selective activation of STAT3 in human monocytes stimulated by G-CSF: implication in inhibition of LPS-induced TNF- production

¹Department of Physiology and ²Clinical Hematology, Osaka City University Medical School, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan

Submitted 11 September 2003 ; accepted in final form 16 January 2004

Lipopolysaccharide (LPS) induced tumor necrosis factor (TNF)- production in human monocytes, which was dependent on activation of extracellular signal-regulated kinase (ERK), p38, c-Jun NH₂-terminal kinase (JNK), and nuclear factor (NF)-B. LPS-induced TNF- production was inhibited by granulocyte colony-stimulating factor (G-CSF) and interleukin (IL)-10. G-CSF, like IL-10, exerted the inhibitory effect even when simultaneously added with LPS. Among the signaling pathways, signal transducer and activator of transcription 3 (STAT3) was selectively activated in monocytes stimulated by G-CSF or IL-10. G-CSF-mediated inhibition of LPS-induced TNF- production as well as G-CSF-induced STAT3 phosphorylation and suppressor of cytokine signaling 3 mRNA expression were prevented by pretreatment of monocytes with AG-490, an inhibitor of Janus kinase 2. G-CSF did not affect LPS-induced activation of ERK, p38, JNK, and NF-B, indicating that G-CSF affects the pathway downstream or independently of these signaling molecules. G-CSF-induced, but not IL-10-induced, STAT3 phosphorylation was attenuated in the presence of LPS. These findings suggest that G-CSF, like IL-10, inhibits LPS-induced TNF- production in human monocytes through selective activation of STAT3, and the immunomodulation observed in vivo by G-CSF administration may be partly ascribed to the direct effect of G-CSF on monocyte functions.

monocytes; granulocyte colony-stimulating factor; interleukin-10; lipopolysaccharide; tumor necrosis factor-; signal transducer and activator of transcription 3

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