IL-6 regulates in vivo dendritic cell differentiation through STAT3 activation
IL-6 regulates in vivo dendritic cell differentiation through STAT3 activation
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DOI：
10.4049/jimmunol.173.6.3844
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发表时间：
2004-09-15
影响因子：
4.4
通讯作者：
Hirano, T
中科院分区：
文献类型：
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作者：
Park, SJ;Nakagawa, T;Hirano, T
树突状细胞（dc）根据其成熟状态协调免疫反应。在对感染的反应中，树突状细胞分化为启动免疫反应的成熟细胞，而在没有感染的情况下，大多数树突状细胞仍处于诱导对自身Ags耐受的不成熟形式。了解是什么控制了这些相反的影响，是疫苗开发和预防不必要的免疫反应的重要目标。一个关键的问题是，在没有感染的情况下，什么细胞因子调节DC成熟。在这项研究中，我们发现IL-6在维持未成熟的dc中起主要作用。IL-6敲除（KO）小鼠成熟DC数量增加，表明IL-6在体内阻断DC成熟。我们在表达IL-6信号传感器gp130的突变版本的敲入小鼠中进一步研究了这种效应，通过Src同源区域2结构域含磷酸酶2/Gab/MAPK （gp130(F759/F759)）或STAT3 （gp130(FxxQ/FxxQ)）的信号缺陷，以及gp130和IL-6缺陷的组合（gp130(F759/F759)/IL-6 KO小鼠）。重要的是，我们发现抑制lps诱导的DC成熟需要IL-6激活STAT3。此外，体内DC中STAT3的磷酸化受IL-6调控，STAT3是IL-6抑制骨髓源性DC激活/成熟所必需的。dc介导的T细胞活化在IL-6 KO小鼠中增强，在gp130（F759/F759）小鼠中抑制。因此，IL-6是体内DC分化的有效调节剂，DC中的IL-6-gp130- stat3信号传导可能是体内控制T细胞介导的免疫反应的关键靶点。
Dendritic cells (DCs) orchestrate immune responses according to their state of maturation. In response to infection, DCs differentiate into mature cells that initiate immune responses, while in the absence of infection, most of them remain in an immature form that induces tolerance to self Ags. Understanding what controls these opposing effects is an important goal for vaccine development and prevention of unwanted immune responses. A crucial question is what cytokine(s) regulates DC maturation in the absence of infection. In this study, we show that IL-6 plays a major role in maintaining immature DCs. IL-6 knockout (KO) mice had increased numbers of mature DCs, indicating that IL-6 blocks DC maturation in vivo. We examined this effect further in knockin mice expressing mutant versions of the IL-6 signal transducer gp130, with defective signaling through either Src homology region 2 domain-containing phosphatase 2/Gab/MAPK (gp130 (F759/F759)) or STAT3 (gp130(FxxQ/FxxQ)), and combined gp130 and IL-6 defects (gp130(F759/F759)/IL-6 KO mice). Importantly, we found STAT3 activation by IL-6 was required for the suppression of LPS-induced DC maturation. In addition, STAT3 phosphorylation in DCs was regulated by IL-6 in vivo, and STAT3 was necessary for the IL-6 suppression of bone marrow-derived DC activation/maturation. DC-mediated T cell activation was enhanced in IL-6 KO mice and suppressed in gp130(F759/F759) mice. IL-6 is thus a potent regulator of DC differentiation in vivo, and IL-6-gp130-STAT3 signaling in DCs may represent a critical target for controlling T cell-mediated immune responses in vivo.