Ursodeoxycholic acid impairs liver-infiltrating T cell chemotaxis through IFNγ and CX3CL1 production in primary biliary cholangitis.

Ursodeoxycholic acid (UDCA) is the primary treatment for primary biliary cholangitis (PBC), but its mechanism of action remains unclear. Studies suggest that UDCA enhances nuclear factor erythroid 2-related factor 2 (NFE2L2) expression and that the interaction between interferon γ (IFNγ) and C-X3-C motif chemokine ligand 1 (CX3CL1) facilitates biliary inflammation in PBC. Therefore, we examined the effects of UDCA on the expression of IFNγ and CX3CL1 in in vitro and in vivo PBC models such as human liver tissue, a murine model, cell lines, and isolated human intrahepatic biliary epithelial cells (IHBECs). We observed a significant decrease in IFNγ mRNA levels and positive correlations between IFNγ and CX3CL1 mRNA levels post-UDCA treatment in PBC livers. NFE2L2-mediated transcriptional activation was significantly enhanced in UDCA-treated Jurkat cells. In 2-octynoic acid-immunized mice, IFNγ production by liver-infiltrating T cells was dependent on NFE2L2 activation. IFNγ significantly and dose-dependently induced CX3CL1 expression, which was significantly decreased in HuCC-T1 cells and IHBECs upon UDCA treatment. These results suggest that UDCA-induced suppression of IFNγ and CX3CL1 production attenuates the chemotactic and adhesive abilities of liver-infiltrating T cells in PBC. This article is protected by copyright. All rights reserved.