[Effect of immune response mediated by ICOS signaling pathway on hepatic fibrosis in mice infected with Schistosoma japonicum].

Objective: To investigate the effect of Th2 polarization mediated by ICOS signaling pathway on hepatic fibrosis in mice infected with Schistosoma japonicum.

Methods: ICOS transgenic (ICOS-Tg) mice and wild-type FVB/NJ mice were used as experimental schistosomiasis model. The sera, livers and spleen lymphocytes of mice were collected, and spleen lymphocytes were stimulated with SEA for 72 h on the day before infection (0 week), and at 4, 7, 12, 16 and 20 weeks post-infection. The concentrations of Th1 cytokines (IFN-gamma and IL-12) and Th2 cytokines (IL-4 and IL-13) in the culture supernatants were measured with sandwich ELISA kit. The levels of SEA-specific antibodies of IgG and its subtypes (IgG1 and IgG2a) in mice sera were measured by ELISA. The concentrations of hyaluronic acid (HA) and hydroxyproline (HYP) in mice sera were measured with sandwich ELISA kit. The expression of alpha-SMA, TGF-beta1 and collagen-I in livers from ICOS-Tg/wild-type mice were assessed by immunohistochemical staining. Liver granulomatous pathology and fibrosis level in ICOS-Tg/wild-type mice was dynamically observed with hematoxylin-eosin (HE) staining and Masson trichrome staining, respectively.

Results: The levels of Th2-type cytokines (IL-4 and IL-13) of ICOS-Tg mice were significantly higher than that of wild-type FVB/NJ mice on 7, 12, 16, and 20 weeks post-infection (P < 0.05). However, Th1 cytokines IFN-gamma and IL-12 showed no significant difference between the two groups (P > 0.05). Th2 differentiation index of ICOS-Tg mice was significantly higher than that of wild-type mice on 7, 12, 16 and 20 weeks post-infection (P < 0.05 or P < 0.01). Compared with wild-type mice, the levels of SEA-specific antibodies of IgG and its subtypes (IgG1 and IgG2a) in ICOS-Tg mice increased significantly (P < 0.05 or P < 0.01, except IgG on 4 and 7 weeks post-infection). Moreover, the ratio of IgG1/IgG2a in ICOS-Tg mice (5.75 +/- 0.94, 4.96 +/- 0.98) were significantly higher than that of wild-type mice (4.31 +/- 0.81, 3.41 +/- 0.83) on 12 and 16 weeks post-infection (P < 0.05). The levels of HA on 7, 12, 16, and 20 weeks post-infection (P < 0.05 or P < 0.01) and HYP on 12, 16, and 20 weeks post-infection (P < 0.05) in ICOS-Tg mice were significantly higher than that of wild-type mice. Immunohistochemical staining showed, from 7 to 20 weeks post-infection, alpha-SMA and TGF-beta1 expression in liver of ICOS-Tg mice was significantly higher than that of wild-type mice (P < 0.05 or P < 0.01); collagen-I level was also higher than wild-type mice. However, there was a significant difference in collagen-I level between the two groups on 20 weeks post-infection (P < 0.05). Furthermore, HE staining showed, on 7, 12, and 16 weeks post-infection, single-egg granuloma volume of ICOS-Tg mice [(28.72 +/- 6.68) x 10(6), (20.47 +/- 5.09) x 10(6) and (12.77 +/- 4.86) x 10(6) microm 3] was significantly higher than that of wild-type mice [(18.04 +/- 6.21) x 10(6), (15.28 +/- 4.87) x 10(6) and (11.24 +/- 4.38) x 10(6) microm 3]. Masson staining showed that level of hepatic fibrosis in ICOS-Tg mice were higher than that of wild-type mice, but the fibrosis scores showed no statistically significant difference between the two groups (P > 0.05).

Conclusion: Th2 immune response is up-regulated in ICOS-Tg mice infected with S. japonicum, and the degree of hepatic fibrosis and related indicators increase. These findings suggest that Th2 polarization mediated by ICOS signaling plays a role in hepatic fibrosis formation in mice infected with S. japonicum.