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This Article Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0901347v1 183/10/6657    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Mencarelli, A. Articles by Fiorucci, S. PubMed PubMed Citation Articles by Mencarelli, A. Articles by Fiorucci, S.

The Bile Acid Sensor Farnesoid X Receptor Is a Modulator of Liver Immunity in a Rodent Model of Acute Hepatitis¹

Andrea Mencarelli,^* Barbara Renga,^* Marco Migliorati,^* Sabrina Cipriani,^* Eleonora Distrutti, Luca Santucci, and Stefano Fiorucci^2*

*Dipartimento di Medicina Clinica e Sperimentale, University of Perugia, Perugia, Italy; and Azienda Ospedaliera di Perugia, Perugia, Italy

Immune-mediated liver diseases including autoimmune and viral hepatitis are a major health problem worldwide. In this study, we report that activation of the farnesoid X receptor (FXR), a member of the ligand-activated nuclear receptor superfamily and bile sensor highly expressed in the liver, attenuates liver injury in a model of autoimmune hepatitis induced by Con A. We found that FXR gene ablation results in a time-dependent increase of liver expression (up to 20-fold in a 9-mo-old mouse) of osteopontin, a NKT cell-derived extracellular matrix protein and immunoregulatory cytokine. In comparison to wild-type, FXR^–/– mice are more susceptible to Con A-induced hepatitis and react to Con A administration by an unregulated production of osteopontin. Administering wild-type mice with a synthetic FXR agonist attenuated Con A-induced liver damage and liver expression of the osteopontin gene. By in vitro studies, we found that FXR is expressed by primarily isolated NKT cells and its ablation favors ostepontin production in response to Con A. Chromatin immunoprecipitation assay and coimmunoprecipitation experiments demonstrate that the short heterodimer partner (SHP), a nuclear receptor and FXR target, was expressed by NKT cell hybridomas and increased in response to FXR activation. FXR activates SHP that interacts with and inhibits c-Jun binding to the osteopontin promoter. These data indicate that in NKT cells, FXR activation causes a SHP-mediated inhibition of osteopontin production. These data support the notion that the bile acid sensor FXR regulates the activation of liver NKT cells.

² Address correspondence and reprint requests to Dr. Stefano Fiorucci, University of Perugia, Dipartimento di Medicina Clinica e Sperimentale, Via E. Dal Pozzo; 06122 Perugia, Italy. E-mail address: fiorucci{at}unipg.it

¹ A.M. has carried out animal studies, cytokine measurement, and flow cytometry and wrote the manuscript. S.C. has performed the immunohistochemistry. B.R. and M.M. carried out RT-PCR, Western blot, ChIP, and coimmunoprecipitation experiments. S.F., E.D., and L.S. designed the study and wrote the manuscript.