Department of Physiology, Osaka City University Graduate School of Medicine, Asahi-machi, Abeno-ku, Japan.
Arch Biochem Biophys. 2010 Mar 15;495(2):144-51. doi: 10.1016/j.abb.2010.01.005. Epub 2010 Jan 12.
We studied the effect of G-CSF on TLR agonist-induced cytokine production in human neutrophils. Human neutrophils produced IL-8 and TNF-alpha in response to stimulation with TLR agonists such as LPS and N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-(R)-cysteinyl-seryl-(lysyl)(3)-lysine. This response was dependent on activation of ERK, p38, and PI3K, but not JNK. TLR agonist-induced cytokine production in neutrophils was inhibited by G-CSF, whereas it was enhanced by GM-CSF, and GM-CSF-mediated enhancement was attenuated by G-CSF. G-CSF and GM-CSF did not affect TLR agonist-induced phosphorylation of ERK, p38, JNK, Akt, and IkappaBalpha. STAT3 activation was much greater in G-CSF-stimulated neutrophils than that in GM-CSF-stimulated cells. G-CSF-mediated STAT3 phosphorylation and inhibition of TLR agonist-induced cytokine production were prevented by pretreatment of cells with AG-490 (JAK2 inhibitor). These findings suggest that G-CSF and GM-CSF exert the opposite effects on TLR agonist-induced cytokine production, and G-CSF negatively regulates TLR agonist-induced cytokine production in neutrophils via activation of STAT3.
我们研究了 G-CSF 对人中性粒细胞 TLR 激动剂诱导细胞因子产生的影响。人中性粒细胞对 TLR 激动剂（如 LPS 和 N-棕榈酰-S-[2,3-双（棕榈酰氧基）-（2RS）-丙基]-（R）-半胱氨酰-丝氨酰-（赖氨酰）（3）-赖氨酸的刺激会产生 IL-8 和 TNF-α。这种反应依赖于 ERK、p38 和 PI3K 的激活，但不依赖于 JNK。G-CSF 抑制 TLR 激动剂诱导的中性粒细胞细胞因子产生，而 GM-CSF 增强其产生，G-CSF 介导的增强作用被 G-CSF 减弱。G-CSF 和 GM-CSF 不影响 TLR 激动剂诱导的 ERK、p38、JNK、Akt 和 IkappaBalpha 的磷酸化。与 GM-CSF 刺激的细胞相比，G-CSF 刺激的中性粒细胞中 STAT3 的激活要强得多。用 AG-490（JAK2 抑制剂）预处理细胞可防止 G-CSF 介导的 STAT3 磷酸化和 TLR 激动剂诱导的细胞因子产生的抑制。这些发现表明，G-CSF 和 GM-CSF 对 TLR 激动剂诱导的细胞因子产生产生相反的影响，G-CSF 通过激活 STAT3 负调控 TLR 激动剂诱导的中性粒细胞细胞因子产生。
