Curcumin Protects Mice Against ConA-induced Hepatitis By Immunomodulatory Effects

Objective:Curcumin is an effective Chinese traditional medicine which has several known biological effects including antiinflammatory, antitumorigenic and antioxidant. However, it is still unknown if curcumin can protect liver of immune injury by immunomodulatory effect. In this study, we established acute liver injury model by injecting Concanavalin A (ConA) and examined the protective effect of curcumin on Con A-induced hepatitis in mice.Methods:70 healthy male mice were randomly divided into four groups. Group A was the vehicle control, in which mice were not administrated ConA or curcumin, but they were given NS and PBS equally. Group B was the curcumin control, in which mice were orally given curcumin (200mg/kg) by gavage, without ConA treatment. Group C was the ConA control group, in which mice were injected tail vein with ConA (20mg/kg), without curcumin treatment. Group D was a treatment group, in which mice were orally given curcumin (200mg/kg) by gavage 30-45 min before being injected with ConA (20mg/kg). The control animals in Group A, B, C were similarly handled, including oral administration of the same volume of NS and tail vein injection with the same volume of PBS. Then the mortality of mice was observed. After 2,8,24 hours mice were sacrificed in batches. The liver injury was examined by measuring serum transaminase, liver histology (HE), and the TNF-a, IFN-y, IL-4 and IL-10 levels in liver tissue were detected by enzyme linked immunosorbent assay (ELISA). Intrahepatic CD4+T and CD8+T lymphocyte proliferation by immunohistochemical were studied. The protein and mRNA level of ICAM-1 and CXCL10 in the liver was detected both by immunohistochemistry and realtime PCR.Results:(1) The treatment of mice with curcumin before ConA injection significantly reduced the elevated plasma levels of aminotransferases compared with ConA control group. In the study, we can see that ALT level of curcumin treatment group was lower than ConA contral group at 8h and 24h (P<0.05) while AST level was lower at 2h,8h and 24h (P<0.05). Furthermore, the treatment of mice with curcumin before ConA can also reduce the incidence of liver necrosis. (2) ELISA showed that curcumin suppressed pro-inflammatory cytokines TNF-a,IFN-yand IL-4 production as compared with the untreated controls (P<0.05 and P<0.01), and augmented synthesis of IL-10 (P<0.05). (3) Curcumin prevented the ConA-induced activation of CD4+ T lymphocytes (P<0.01). Compared with vehicle control and curcumin control, ConA-induced mice could accumulate CD8+ T lymphocyte (P<0.05). However, there was no evidence that curcumin prevent the ConA-induced activation of CD8+T lymphocytes (P>0.05). (4) Compared with ConA control, treatment of curcumin could reduce intrahepatic ICAM-1 and CXCL10 expression. Meanwhile realtime PCR showed that curcumin downgrated adhesion ICAM-1 (P<0.05) and cytomkine CXCL10 expression (P<0.01).Conclusion:(1) ConA-induced mice developes autoimmune hepatitis accompanied by dramatic accumulation of T lymphocytes especially for CD4+ T lymphocytes, which can be a better model of human autoimmune liver disease. (2) Curcumin alleviates the severity of hepatic inflammation in experimental hepatitis induced by ConA, which suppresses pro-inflammatory cytokines TNF-a,IFN-yand IL-4 production and augments synthesis of IL-10. (3) Curcumin can prevent the ConA-induced activation of lymphocytes especially for CD4+ T lymphocytes by modulating lymphocyte homing. (4) Curcumin impacting lymphocyte homing may likely be mediated via inhibition of the expression of adhesion ICAM-1 and chemokine CXCL10 consequently inhibition CD4+ T lymphocytes activation.