Selective activation of STAT3 in human monocytes stimulated by G-CSF:: implication in inhibition of LPS-induced TNF-α production
Selective activation of STAT3 in human monocytes stimulated by G-CSF:: implication in inhibition of LPS-induced TNF-α production
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DOI：
10.1152/ajpcell.00387.2003
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发表时间：
2004-06-01
影响因子：
5.5
通讯作者：
Kitagawa, S
中科院分区：
文献类型：
--
作者：
Nishiki, S;Hato, F;Kitagawa, S
脂多糖（LPS）诱导人单核细胞产生肿瘤坏死因子（TNF）-α，这依赖于细胞外信号调节激酶（ERK）、p38、c-Jun NH 2-末端激酶（JNK）和核因子（NF）-kappaB的激活。粒细胞集落刺激因子（G-CSF）和白细胞介素（IL）-10抑制LPS诱导的TNF-α产生。G-CSF与IL-10一样，即使同时加入LPS也能发挥抑制作用。在这些信号通路中，G-CSF或IL-10可选择性激活单核细胞中的信号转导子和转录激活子3（STAT 3）。用Janus激酶2抑制剂AG-490预处理单核细胞，可阻止G-CSF介导的LPS诱导的TNF-α产生抑制以及G-CSF诱导的STAT 3磷酸化和细胞因子信号传导抑制因子3 mRNA表达抑制。G-CSF不影响LPS诱导的ERK、p38、JNK和NF-κ B的活化，表明G-CSF影响这些信号分子下游或独立的通路。G-CSF诱导的，但不是IL-10诱导的，STAT 3磷酸化在LPS存在下减弱。这些发现表明，G-CSF，像IL-10一样，通过选择性激活STAT 3抑制LPS诱导的人单核细胞中TNF-α的产生，并且通过G-CSF给药在体内观察到的免疫调节可能部分归因于G-CSF对单核细胞功能的直接作用。
Lipopolysaccharide (LPS) induced tumor necrosis factor (TNF)-alpha 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)-kappaB. LPS-induced TNF-alpha 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-alpha 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-kappaB, 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-alpha 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.