Baoganning formula alleviates liver fibrosis in mice by inhibiting hepatic IDO1 expression and promoting phenotypic maturation of dendritic cells

Abstract

To investigate the protective effect of Bao Gan Ning (BGN), a traditional Chinese medicinal formula, against CCl4-induced liver fibrosis in mice and explore the mechanism. C57BL/6 mice were randomly divided into control group, liver fibrosis model group, positive control group and the low-, middle-, and high-dose BGN groups (n=10). In all but the control group, the mice were subjected to daily intraperitoneal injection of 25% CCl4 (in olive oil) to induce liver fibrosis and intragastric gavage of corresponding drugs. After 8 weeks, serum levels of ALT and AST were detected. Pathological examination of the liver was performed using HE and Sirius Red staining and α-SMA immunohistochemistry. The expression level of indoleamine 2, 3-dioxygenase 1 (IDO1) and phenotypic changes of hepatic DCs in the liver were measured. Another 18 mice were randomly divided into AAV9-NC, AAV9-IDO1 and high-dose BGN + AAV-IDO1 groups (n=6) for corresponding treatment, and 4 weeks later the deposit of hepatic IDO1 and phenotypic changes of the hepatic DCs were analyzed. Compared with those in the model group, serum AST and ALT levels decreased significantly in BGN group (P < 0.01). Obvious liver fibrosis was observed in the model group, while the mice treated with BGN showed obviously reduced cell necrosis and collagen proliferation in the liver with significantly lowered the expression levels of hepatic α-SMA and IDO1 (P < 0.05). The percentages of CD11C + DCs, CD11C +CD80 + DCs, CD11C +CD86 + DCs, CD11C +CD40 + DCs, CD11C +MHCII + DCs, CD3 + T cells, and CD3 +CD4 + T cells all increased significantly in BGN group as compared with the model group (P < 0.05). In mice with adenovirus-mediated IDO1 overexpression in the liver, BGN treatment significantly lowered the expression level of IDO1 (P=0.000) and increased the percentages of hepatic CD11C +CD40 + DCs, CD11C +MHCII + DCs and CD3 +CD4 + T cells (P < 0.05). BGN can effectively inhibit liver fibrosis in mice possibly by lowering the expression level of IDO1 in the liver, thus improving the function of hepatic DCs and subsequently promoting proliferation of T cells.