Transforming growth factor beta is dispensable for the molecular orchestration of Th17 cell differentiation.
Transforming growth factor beta is dispensable for the molecular orchestration of Th17 cell differentiation.
复制标题
转化生长因子β对于 Th17 细胞分化的分子协调是不可或缺的。
DOI：
10.1084/jem.20082286
复制
发表时间：
2009-10-26
影响因子：
15.3
通讯作者：
Das, Gobardhan
中科院分区：
文献类型：
--
作者：
Das, Jyoti;Ren, Guangwen;Zhang, Liying;Roberts, Arthur I.;Zhao, Xin;Bothwell, Alfred L. M.;Van Kaer, Luc;Shi, Yufang;Das, Gobardhan
产生白细胞介素（IL）-17的辅助性T（Th 17）细胞在几种自身免疫性疾病的病理生理学中起关键作用。Th 17细胞的分化需要同时存在一种不寻常的细胞因子组合：IL-6（一种促炎细胞因子）和转化生长因子（TGF）β（一种促炎细胞因子）。然而，TGF-β发挥其对Th 17细胞分化的作用的分子机制仍不清楚。我们报道TGF-β不直接促进Th 17细胞分化，而是通过阻断转录因子信号转导子和转录激活子（STAT）4和加塔-3的表达间接起作用，从而阻止Th 1和Th 2细胞分化。相反，TGF-β对视黄酸受体相关孤儿核受体γt（一种Th 17特异性转录因子）的表达无影响。有趣的是，在不能产生Th 1和Th 2细胞的Stat-6−/−T-bet−/−小鼠中，单独的IL-6足以诱导Th 17细胞的稳健分化，而TGF-β没有影响，这表明TGF-β对Th 17细胞的发育是不利的。因此，BALB/c Stat-6−/−T-bet−/−小鼠（而非野生型BALB/c小鼠）对实验性自身免疫性脑脊髓炎的发生高度易感，其可被抗IL-17抗体阻断，但不能被抗TGF-β抗体阻断。总的来说，这些数据提供了TGF-β不是Th 17细胞分化的分子协调所直接需要的证据。
Interleukin (IL)-17–producing T helper (Th17) cells play a critical role in the pathophysiology of several autoimmune disorders. The differentiation of Th17 cells requires the simultaneous presence of an unusual combination of cytokines: IL-6, a proinflammatory cytokine, and transforming growth factor (TGF) β, an antiinflammatory cytokine. However, the molecular mechanisms by which TGF-β exerts its effects on Th17 cell differentiation remain elusive. We report that TGF-β does not directly promote Th17 cell differentiation but instead acts indirectly by blocking expression of the transcription factors signal transducer and activator of transcription (STAT) 4 and GATA-3, thus preventing Th1 and Th2 cell differentiation. In contrast, TGF-β had no effect on the expression of retinoic acid receptor–related orphan nuclear receptor γt, a Th17-specific transcription factor. Interestingly, in Stat-6−/−T-bet−/− mice, which are unable to generate Th1 and Th2 cells, IL-6 alone was sufficient to induce robust differentiation of Th17 cells, whereas TGF-β had no effect, suggesting that TGF-β is dispensable for Th17 cell development. Consequently, BALB/c Stat-6−/−T-bet−/− mice, but not wild-type BALB/c mice, were highly susceptible to the development of experimental autoimmune encephalomyelitis, which could be blocked by anti–IL-17 antibodies but not by anti–TGF-β antibodies. Collectively, these data provide evidence that TGF-β is not directly required for the molecular orchestration of Th17 cell differentiation.
登录
查看更多内容
影响因子：
30.5
作者：
Acosta-Rodriguez, Eva V.;Napolitani, Giorgio;Sallusto, Federica
通讯作者：
Sallusto, Federica
影响因子：
32.4
作者：
Gorelik, L;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
32.4
作者：
Li, Ming O.;Wan, Yisong Y.;Flavell, Richard A.
通讯作者：
Flavell, Richard A.
影响因子：
56.9
作者：
Pasare, C;Medzhitov, R
通讯作者：
Medzhitov, R
影响因子：
15.9
作者：
Burlingham, William J.;Love, Robert B.;Willkes, David S.
通讯作者：
Willkes, David S.