Up-regulation of IL-10R1 expression is required to render human neutrophils fully responsive to IL-10
Up-regulation of IL-10R1 expression is required to render human neutrophils fully responsive to IL-10
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DOI：
10.4049/jimmunol.167.4.2312
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发表时间：
2001-08-15
影响因子：
4.4
通讯作者：
Cassatella, MA
中科院分区：
文献类型：
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作者：
Crepaldi, L;Gasperini, S;Cassatella, MA
我们最近发现，IL-10未能触发Stat 3和Stat 1酪氨酸磷酸化在新鲜分离的人中性粒细胞。在这项研究中，我们报告说，IL-10仍然可以诱导Stat 3酪氨酸磷酸化和Stat 1和Stat 3的IFN-γ反应区或c-sis诱导元件的高亲和力合成衍生物的中性粒细胞，已培养了至少3小时与LPS的结合。类似地，IL-10上调细胞因子信号传导抑制因子（SOCS）-3 mRNA的能力在培养的嗜中性粒细胞中显著增强，并因此翻译成SOCS-3蛋白。由于中性粒细胞获得对IL-10的反应性需要从头蛋白质合成，我们评估了IL-10 R1或IL-10 R2的表达是否在培养的中性粒细胞中被调节。我们在循环中性粒细胞中检测到组成性IL-10 R1 mRNA和蛋白表达，其水平远低于在自体单核细胞或淋巴细胞中观察到的水平。相比之下，IL-10 R2表达在两种细胞类型中相当。然而，IL-10 R1（而不是IL-10 R2）的mRNA和蛋白质的表达显着增加，在中性粒细胞由LPS刺激。IL-10激活Stat 3酪氨酸磷酸化和SOCS-3合成以及调节LPS处理的中性粒细胞中IL-1受体拮抗剂和巨噬细胞炎性蛋白1 β释放的能力与IL-10 R1表达的增加相关，并且通过中和抗IL-10 R1和抗IL-10 R2 Ab消除。我们的研究结果表明，中性粒细胞响应IL-10的能力，如通过Stat 3酪氨酸磷酸化，SOCS-3表达和细胞因子产生的调节所评估的，非常依赖于IL-10 R1的表达水平。
We have recently shown that IL-10 fails to trigger Stat3 and Stat1 tyrosine phosphorylation in freshly isolated human neutrophils. In this study, we report that IL-10 can nonetheless induce Stat3 tyrosine phosphorylation and the binding of Stat1 and Stat3 to the IFN-gamma response region or the high-affinity synthetic derivative of the c-sis-inducible element in neutrophils that have been cultured for at least 3 h with LPS. Similarly, the ability of IL-10 to up-regulate suppressor of cytokine signaling (SOCS)-3 mRNA was dramatically enhanced in cultured neutrophils and, as a result, translated into the SOCS-3 protein. Since neutrophils' acquisition of responsiveness to IL-10 required de novo protein synthesis, we assessed whether expression of IL-10R1 or IL-10R2 was modulated in cultured neutrophils. We detected constitutive IL-10R1 mRNA and protein expression in circulating neutrophils, at levels which were much lower than those observed in autologous monocytes or lymphocytes. In contrast, IL-10R2 expression was comparable in both cell types. However, IL-10R1 (but not IL-10R2) mRNA and protein expression was substantially increased in neutrophils stimulated by LPS. The ability of IL-10 to activate Stat3 tyrosine phosphorylation and SOCS-3 synthesis and to regulate IL-1 receptor antagonist and macrophage-inflammatory protein 1 beta release in LPS-treated neutrophils correlated with this increased IL-10R1 expression, and was abolished by neutralizing anti-IL-10R1 and anti-IL-10R2 Abs. Our results demonstrate that the capacity of neutrophils to respond to IL-10, as assessed by Stat3 tyrosine phosphorylation, SOCS-3 expression, and modulation of cytokine production, is very dependent on the level of expression of IL-10R1.