[Regulating the immune response to carbon tetrachloride-induced liver fibrosis in mice by blocking inducible co-stimulatory molecules and interleukin-33].

Objective: To investigate the effects of combined blockade of interleukin-33 (IL-33) and inducible co-stimulatory molecule (ICOS) on carbon tetrachloride-induced chronic liver fibrosis and imbalance of T helper lymphocyte subsets in mice. Methods: There were 40 BALB/c mice in each model and control group. Flow cytometry was used to determine the proportion of Th1/Th2/Th17 cells in the splenic lymphocyte suspension of mice, the expression levels of interferon γ, IL-4, and IL-17 in the splenic lymphocyte suspension of liver fibrosis mice after combined blockade of IL-33 and ICOS, and the pathological changes of liver histopathology in mice with liver fibrosis. Two independent sample t-test was used to compare data between groups. Results: Compared with the non-blocking group, the proportion of Th2 and Th17 cells in the IL-33/ICOS blocking group was significantly down-regulated (Th2: 65.96% ± 6.04% vs. 49.09% ± 7.03%; Th17: 19.17% ± 4.03% vs. 9.56% ± 2.03%), while the proportion of Th1 cells and Th1/Th2 ratio were up-regulated (Th1: 17.14% ± 3.02% vs. 31.93% ± 5.02%; Th1/Th2: 0.28 ± 0.06 vs. 0.62 ± 0.23), and the difference was statistically significant (t = 5.15, 6.03, 7.14, 4.28, respectively, with P < 0.05). After entering the chronic inflammation stage of liver fibrosis in mice (10 weeks), compared with the non-blocking group, the expression levels of IL-4 and IL-17 in the blockade group were significantly down-regulated [IL-4: (84.75 ± 14.35) pg/ ml vs. (77.88 ± 19.61) pg/ml; IL-17: (72.38 ± 15.13) pg/ml vs. (36.38 ± 8.65) pg/ml], while the expression of interferon γ was up-regulated [(37.25 ± 11.51) pg/ml vs. (77.88 ± 19.61) pg/ml], and the difference was statistically significant (t: IL-4: 4.71; IL-17: 5.84; interferon γ: 5.05, respectively, with P < 0.05). Liver histopathological results showed that hepatic necrosis, hepatic lobular structural disorder, and fibrous tissue hyperplasia were significantly lower in the blockade group than those in the non-blocking group at 13 weeks of liver fibrosis. Conclusion: Combined blockade of the ICOS signaling pathway and IL-33 can regulate Th2 and Th17 polarization, down-regulate the inflammatory response, and inhibit or prevent the occurrence and progression of fibrosis.目的： 探讨联合阻断白细胞介素33（IL-33）、可诱导共刺激分子(ICOS)对四氯化碳致小鼠慢性肝纤维化及辅助性T淋巴细胞亚群失衡的影响。 方法： 模型组与正常组BALB/c小鼠各40只，流式细胞仪分析测定小鼠脾淋巴细胞悬液中Th1/Th2/Th17细胞比例、联合阻断IL-33与ICOS后肝纤维化小鼠脾淋巴细胞悬液中干扰素γ、IL-4、IL-17表达水平以及肝纤维化小鼠肝组织病理变化。组间数据比较采用两独立样本t检验。 结果： 与未阻断组相比，阻断IL-33/ICOS组Th2、Th17细胞比例明显下调（Th2：65.96%±6.04%与49.09%±7.03%；Th17: 19.17%±4.03%与9.56%±2.03%），Th1细胞比例及Th1/Th2比值上调（Th1：17.14%±3.02%与31.93%±5.02%；Th1/Th2：0.28±0.06与0.62±0.23），差异有统计学意义（t值分别为5.15、6.03、7.14、4.28，P值均< 0.05）。进入慢性炎症阶段（10周）后，与未阻断组相比，阻断组肝纤维化小鼠IL-4、IL-17的表达水平明显下调[IL-4：（84.75±14.35）pg/ml与（77.88±19.61）pg/ml；IL-17：（72.38±15.13）pg/ml与(36.38±8.65) pg/ml]，干扰素γ的表达水平上调[（37.25±11.51）pg/ml与（77.88±19.61）pg/ml]，差异有统计学意义（t值分别为：IL-4：4.71；IL-17：5.84；干扰素γ：5.05，P值均< 0.05）。肝组织病理结果显示：阻断组在肝纤维化13周时肝细胞坏死情况、肝小叶结构紊乱情况及纤维组织增生较未阻断组明显减轻。 结论： 联合阻断ICOS信号通路及IL-33可调节Th2及Th17极化，下调炎症反应，抑制或防止纤维化的发生与进展。.