The C-terminal module IV of connective tissue growth factor is a novel immune modulator of the Th17 response
The C-terminal module IV of connective tissue growth factor is a novel immune modulator of the Th17 response
复制标题
结缔组织生长因子的C端模块IV是Th17反应的新型免疫调节剂
作者：
R. Rodrigues;Raúl R. Rodrigues;S. Rayego‐Mateos;B. Suarez;Carolina Lavoz;L. Aroeira;E. Sanchez;M. Orejudo;M. Alique;C. López;A. Ortiz;J. Egido;M. Ruíz
结缔组织生长因子（CTGF/CCN 2）是一种易被蛋白水解降解的基质细胞蛋白。CCN 2水平已被认为是几种慢性疾病的潜在风险生物标志物。在体液中，可以发现CCN 2全长及其降解片段;然而，它们的体内作用远未阐明。CCN 2被描述为促纤维化介质，但这一概念正在转变为促炎细胞因子。在体外，CCN 2全长及其C-末端模块IV（CCN 2（IV））发挥促炎特性。新出现的证据表明，Th 17细胞及其效应细胞因子IL-17 A参与慢性炎症性疾病。我们的目的是探索CCN 2（IV）是否可以调节Th 17应答。在体外，用CCN 2（IV）刺激人幼稚CD 4 + T淋巴细胞导致分化为Th 17表型。在C57 BL/6小鼠中研究了CCN 2（IV）的体内作用。腹腔注射重组CCN 2（IV）不改变血清IL-17 A水平，但引起肾脏中Th 17应答的激活，其特征在于Th 17（IL 17 A +/CD 4+）细胞的间质浸润和促炎介质的上调。在CCN 2（IV）注射小鼠中，发现Th 17相关因子（IL-17 A、IL-6、STAT 3和RORγt）的肾脏水平升高，而Th 1/Th 2细胞因子或Treg相关因子（TGF-β和Foxp-3）未发生变化。用抗IL-17 A中和抗体治疗减少了CCN 2（IV）诱导的肾脏炎症。我们的研究结果揭示了CCN 2的C-末端模块诱导人Th 17细胞的Th 17分化并引起肾脏Th 17炎症反应。此外，这些数据证明IL-17 A靶向是治疗慢性炎性疾病（包括肾脏病理）的有前景的工具。
Connective tissue growth factor (CTGF/CCN2) is a matricellular protein susceptible to proteolytic degradation. CCN2 levels have been suggested as a potential risk biomarker in several chronic diseases. In body fluids, CCN2 full-length and its degradation fragments can be found; however, their in vivo effects are far from being elucidated. CCN2 was described as a profibrotic mediator, but this concept is changing to a proinflammatory cytokine. In vitro, CCN2 full-length and its C-terminal module IV (CCN2(IV)) exert proinflammatory properties. Emerging evidence suggest that Th17 cells, and its effector cytokine IL-17A, participate in chronic inflammatory diseases. Our aim was to explore whether CCN2(IV) could regulate the Th17 response. In vitro, stimulation of human naive CD4+ T lymphocytes with CCN2(IV) resulted in differentiation to Th17 phenotype. The in vivo effects of CCN2(IV) were studied in C57BL/6 mice. Intraperitoneal administration of recombinant CCN2(IV) did not change serum IL-17A levels, but caused an activation of the Th17 response in the kidney, characterized by interstitial infiltration of Th17 (IL17A+/CD4+) cells and upregulation of proinflammatory mediators. In CCN2(IV)-injected mice, elevated renal levels of Th17-related factors (IL-17A, IL-6, STAT3 and RORγt) were found, whereas Th1/Th2 cytokines or Treg-related factors (TGF-β and Foxp-3) were not modified. Treatment with an anti-IL-17A neutralizing antibody diminished CCN2(IV)-induced renal inflammation. Our findings unveil that the C-terminal module of CCN2 induces the Th17 differentiation of human Th17 cells and causes a renal Th17 inflammatory response. Furthermore, these data bear out that IL-17A targeting is a promising tool for chronic inflammatory diseases, including renal pathologies.
登录
查看更多内容
影响因子：
19.6
作者：
Dong, Xiangyang;Bachman, Lori A.;Miller, Melinda N.;Nath, Karl A.;Griffin, Matthew D.
通讯作者：
Griffin, Matthew D.
DOI：
10.1073/pnas.94.24.12981
发表时间：
1997-11-25
影响因子：
11.1
作者：
Kim, HS;Nagalla, SR;Rosenfeld, RG
通讯作者：
Rosenfeld, RG
DOI：
10.1053/j.ajkd.2010.11.022
发表时间：
2011-06
期刊：
American journal of kidney diseases : the official journal of the National Kidney Foundation
影响因子：
--
作者：
O'Seaghdha CM;Hwang SJ;Bhavsar NA;Köttgen A;Coresh J;Astor BC;Fox CS
通讯作者：
Fox CS
影响因子：
2.8
作者：
Booth AJ;Bishop DK
通讯作者：
Bishop DK
影响因子：
15.9
作者：
Li, Li;Huang, Liping;Okusa, Mark D.
通讯作者：
Okusa, Mark D.