IL-6-gp130-STAT3 in T cells directs the development of IL-17+Th with a minimum effect on that of Treg in the steady state
IL-6-gp130-STAT3 in T cells directs the development of IL-17+Th with a minimum effect on that of Treg in the steady state
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DOI：
10.1093/intimm/dxm045
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发表时间：
2007-06-01
影响因子：
4.4
通讯作者：
Hirano, Toshio
中科院分区：
文献类型：
--
作者：
Nishihara, Mika;Ogura, Hideki;Hirano, Toshio
产生IL-17的T-h（T（h）17）包括促炎性T-h的独特谱系，其是自身免疫性疾病的主要贡献者。用IL-6和转化生长因子β（TGF β）处理诱导初始CD 4（+）T细胞产生Th 17，这也需要IL-6/TGF β靶向ROR γ t的表达。我们报道了IL-6通过信号转导子gp 130的酪氨酸残基转导两条信号通路：一条依赖于信号转导子和转录激活子（STAT）-3的激活，另一条依赖于Src同源区2结构域磷酸酶2（SHP 2）/Grb 2相关结合物（Gab）/丝裂原活化蛋白激酶（MAPK）的激活。在这里，我们发现携带突变型gp 130的CD 4 + T细胞不能发育成Th 17，而携带突变型gp 130的CD 4 + T细胞只能产生Th 17，突变型gp 130转导SHP 2/Gab/MAPK通路，而不能转导STAT 3介导的通路。表明IL-6通过STAT 3活化所需的gp 130的酪氨酸残基直接作用于T细胞，以促进Th 17的发育。此外，我们发现，gp 130-STAT 3途径是必不可少的Th 17的发展和表达ROR γ t通过使用T细胞特异性缺乏gp 130和STAT 3。值得注意的是，调节性T细胞（Treg）的百分比和数量在我们体内测试的所有突变小鼠之间是相当的，尽管我们表明IL-6-gp 130-STAT 3途径抑制Treg的体外发育。因此，我们的结论是，IL-6的行为直接促进Th 17的发展，通过激活T细胞gp 130-STAT 3途径，但有一个最小的影响，至少在体内稳态Treg的发展。因此，阻断CD 4 + T细胞中的IL-6-gp 130-STAT 3通路可能是控制不需要的T（h）17介导的免疫应答（包括自身免疫性疾病）的良好靶点。
IL-17-producing T-h (T(h)17) comprise a distinct lineage of pro-inflammatory T-h that are major contributors to autoimmune diseases. Treatment with IL-6 and transforming growth factor beta (TGF beta) induces naive CD4(+) T cells to generate Th17, which also requires expression of the IL-6/TGF[3 target ROR gamma t. We reported that IL-6 transduces two signaling pathways via tyrosine redidues of the signal transducer gp130: one depends on signal transducers and activators of transcription (STAT)-3 activation and the other on Src homology region 2 domain-containing phosphatase 2 (SHP2)/Grb2 associated binder (Gab)/mitogen-activated protein kinase (MAPK) activation. Here, we showed that CD4+ T cells carrying a mutant gp130 that transduces the SHP2/Gab/MAPK pathway but not the STAT3-mediated one failed to develop into Th17, while CD4+ T cells whose mutant gp130 transduces the STAT3 signal only generated Th17, indicating that IL-6 acts directly on T cells through the tyrosine residues of gp130 required for STAT3 activation to promote the development of Th17. Moreover, we found that gp130-STAT3 pathway is essential for Th17 development and for the expression of ROR gamma t by using T cells specifically lacking gp130 and STAT3. Noteworthy is that the regulatory T cell (Treg) percentages and numbers were comparable between all mutant mice we tested in vivo, although we showed that IL-6-gp130-STAT3 pathway suppressed Treg development in vitro. Thus, we conclude that IL-6 acts directly to promote the development of Th17 by activating the T cell gp130-STAT3 pathway but has a minimum effect on Treg development at least in the steady state in vivo. Therefore, blockade of IL-6-gp130-STAT3 pathway in CD4+ T cells could be a good target for controlling unwanted T(h)17-mediated immune responses including autoimmune diseases.