Zhang Yuxia, Huang Dake, Gao Wenda, Yan Jun, Zhou Wanling, Hou Xin, Liu Miao, Ren Cuiping, Wang Siying, Shen Jijia
School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, PR China.
Antagen Institute for Biomedical Research, Boston, MA 02118, USA.
Int Immunol. 2015 Jul;27(7):317-25. doi: 10.1093/intimm/dxv017. Epub 2015 Apr 3.
Accumulating evidence has identified the profibrogenic properties of IL-17A in organ fibrosis. However, the role of IL-17A signal in liver fibrosis induced by Schistosoma japonicum infection remains unclear. In this study, we investigated liver fibrosis in wild-type (WT) and IL-17RA(-/-) mice upon S. japonicum infection. Hepatic IL-17A, IL-17C, IL-17E (IL-25), IL-17F, IL-17RA, IL-17RB and IL-17RC transcript levels were determined by RT-PCR. IL-17A(+) cells were analyzed by flow cytometry and confocal microscopy among granuloma cells. Immunostaining of IL-17R was performed on liver sections. Collagen deposition was assessed by Van Gieson's staining. IL-17A, IL-17C, IL-17E, IL-17F, IL-17RA and IL-17RC mRNA levels were dramatically increased in fibrotic livers. Among granuloma cells, CD3(+) and CD3(-) lymphocytes, neutrophils and macrophages were found to express IL-17A. Compared to WT, IL-17RA(-/-) mice displayed attenuated granulomatous inflammation, liver fibrosis, improved liver function and high survival. Meanwhile, α-smooth muscle actin staining and the expression of fibrogenic genes (transforming growth factor β, IL-13 and collagen-I) as well as IL-17A-induced proinflammatory mediators (IL-1β, IL-6, tumor necrosis factor α, CXCL1 and CXCL2) and proteinases (MMP3 and TIMP1) involved in fibrosis were markedly reduced in IL-17RA(-/-) mice. In addition, Th2 cytokines IL-4 and IL-17E (IL-25) were also decreased in IL-17RA(-/-) mice. These results indicated that IL-17A signal contributes to the pathogenesis of liver fibrosis in murine schistosomiasis. This effect was induced possibly by activating hepatic stellate cells and stimulating the release of proinflammatory cytokines and chemokines. Furthermore, the Th2 response was also enhanced by IL-17A signals. Our data demonstrate that IL-17A may serve as a promising target for antifibrotic therapy.
越来越多的证据表明白细胞介素-17A（IL-17A）在器官纤维化中具有促纤维化特性。然而，IL-17A信号在日本血吸虫感染诱导的肝纤维化中的作用仍不清楚。在本研究中，我们调查了野生型（WT）和IL-17RA基因敲除（-/-）小鼠感染日本血吸虫后的肝纤维化情况。通过逆转录-聚合酶链反应（RT-PCR）测定肝脏中IL-17A、IL-17C、IL-17E（IL-25）、IL-17F、IL-17RA、IL-17RB和IL-17RC的转录水平。通过流式细胞术和共聚焦显微镜分析肉芽肿细胞中的IL-17A阳性细胞。对肝脏切片进行IL-17R免疫染色。通过Van Gieson染色评估胶原沉积。纤维化肝脏中IL-17A、IL-17C、IL-17E、IL-17F、IL-17RA和IL-17RC的mRNA水平显著升高。在肉芽肿细胞中，发现CD3阳性和CD3阴性淋巴细胞、中性粒细胞和巨噬细胞表达IL-17A。与WT小鼠相比，IL-17RA（-/-）小鼠的肉芽肿性炎症、肝纤维化减轻，肝功能改善，生存率提高。同时，IL-17RA（-/-）小鼠中α-平滑肌肌动蛋白染色以及纤维化相关基因（转化生长因子β、IL-13和I型胶原）的表达，以及IL-17A诱导的促炎介质（IL-1β、IL-6、肿瘤坏死因子α、CXCL1和CXCL2）和参与纤维化的蛋白酶（基质金属蛋白酶3和金属蛋白酶组织抑制因子1）均明显降低。此外，IL-17RA（-/-）小鼠中的Th2细胞因子IL-4和IL-17E（IL-25）也减少。这些结果表明IL-17A信号参与了小鼠血吸虫病肝纤维化的发病机制。这种作用可能是通过激活肝星状细胞并刺激促炎细胞因子和趋化因子的释放而诱导的。此外，IL-17A信号也增强了Th2反应。我们的数据表明IL-17A可能是抗纤维化治疗的一个有前景的靶点。
