Cellular Biology in Renal Diseases Laboratory, Instituto de Investigacion Sanitaria Fundación Jiménez Díaz, Universidad Autónoma Madrid, Madrid, Spain.
Lab Invest. 2013 Jul;93(7):812-24. doi: 10.1038/labinvest.2013.67. Epub 2013 May 6.
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.
结缔组织生长因子（CTGF/CCN2）是一种细胞外基质蛋白，易发生蛋白水解降解。CCN2 水平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 CCN2 全长及其降解片段；然而，它们的体内作用还远未阐明。CCN2 被描述为一种促纤维化介质，但这一概念正在向促炎细胞因子转变。在体外，CCN2 全长及其 C 端模块 IV（CCN2(IV)）发挥促炎作用。新出现的证据表明，Th17 细胞及其效应细胞因子 IL-17A 参与慢性炎症性疾病。我们的目的是探讨 CCN2(IV) 是否可以调节 Th17 反应。在体外，用 CCN2(IV)刺激人幼稚 CD4+T 淋巴细胞可诱导 Th17 表型分化。在 C57BL/6 小鼠中研究了 CCN2(IV)的体内作用。重组 CCN2(IV)腹腔内给药不会改变血清 IL-17A 水平，但会导致肾脏 Th17 反应的激活，表现为 Th17（IL17A+/CD4+）细胞间质浸润和促炎介质上调。在 CCN2(IV)注射小鼠中，发现肾脏中 Th17 相关因子（IL-17A、IL-6、STAT3 和 RORγt）水平升高，而 Th1/Th2 细胞因子或 Treg 相关因子（TGF-β和 Foxp-3）没有改变。用抗 IL-17A 中和抗体治疗可减少 CCN2(IV)诱导的肾脏炎症。我们的研究结果揭示，CCN2 的 C 端模块诱导人 Th17 细胞的 Th17 分化，并导致肾脏 Th17 炎症反应。此外，这些数据表明，针对 IL-17A 的治疗是一种有前途的治疗慢性炎症性疾病（包括肾脏疾病）的工具。
