(839.1) Estrogen Sulfotransferase is Required for the Female Mice Sensitivity to T Cell-Mediated Hepatitis in an Estrogen-Independent Manner

Poster Board Number: B95

Jingyuan Wang (University of Pittsburgh), Jibin Guan (University of Pittsburgh), Ziteng Zhang (University of Pittsburgh), Wen Xie (University of Pittsburgh)

Introduction

Autoimmune hepatitis (AIH) is a severe T cell-mediated chronic liver disease with a higher incidence in females. However, the pathological mechanism of AIH remains elusive and there is no effective therapy except for nonspecific immunosuppression. Estrogen sulfotransferase (EST or SULT1E1) is a phase II enzyme best known for its function in sulfonating and deactivating estrogens. Previous work from our lab showed that EST is inducible and functional in several other inflammation diseases. However, the possible role and mechanism of EST in T-cell mediated hepatitis remain unknown. The goal of this study is to investigate the role of EST in the female preference of T-cell mediated hepatitis.

Methods

Concanavalin A (ConA) was used to induce T cell-mediated hepatitis in female C57BL/6J mice. For Est loss of function models, we used the whole-body or liver-specific Est knockout mice, or treating WT mice with the Est inhibitor Triclosan. We also used Est whole-body knockout mice with Est specifically  reconstituted in the hepatocytes. The severity of liver injury was evaluated through the serum levels of Alanine transaminase (ALT), Aspartate transaminase (AST) and the necrosis in liver histology. Inflammatory responses were characterized by the levels of cytokines and infiltrated immune cells in the liver by real-time PCR, ELISA, and flow cytometry. To test the role of estrogens in the regulation, we depleted estrogens by ovariectomy in female mice prior to the ConA challenging.

Results

Est was highly induced in the liver of ConA-treated mice. Knockout or pharmacological inhibition of Est significantly protected the female mice from ConA-induced hepatitis regardless of ovariectomy. Moreover, ESTKO mice exhibited a more robust inflammatory response with a larger spleen-to-body-weight ratio and a higher level of pro-inflammatory cytokines production. ESTKO mice had a higher frequency of CD4+ T cells, including a higher level of Treg population, and less cytotoxic CD8+ T cells. The protective phenotype of ESTKO mice was abolished when the expression of EST was reconstituted in the hepatocytes.

Conclusions

Hepatic EST is required for female sensitivity to Con A-induced T-cell mediated hepatitis in an estrogen-independent manner. Pharmacological inhibition of EST might be a potential strategy for the treatment of AIH.