Mengxi Jiang1, Marcus Klein2, Ulrich M Zanger2, Mohammad K Mohammad3, Matthew C Cave3, Nilesh W Gaikwad4, Natasha J Dias5, Kyle W Selcer5, Yan Guo6, Jinhan He7, Xiuhui Zhang8, Qiujin Shen9, Wenxin Qin9, Jiang Li1, Song Li1, Wen Xie10. 1. Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA. 2. Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tuebingen, Tuebingen, Germany. 3. Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine Louisville, KY, USA. 4. Department of Nutrition and Department of Environmental Toxicology, University of California, Davis, CA, USA. 5. Department of Biological Sciences, Duquesne University, Pittsburgh, PA, USA. 6. Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 7. Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan, China. 8. Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, China. 9. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 10. Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: wex6@pitt.edu.
Abstract
BACKGROUND & AIMS: Chronic inflammatory liver diseases are associated with estrogen excess and feminization in men, which is thought to be due to compromised liver function to break down estrogens. The goal of this study is to determine whether the inflammatory induction of steroid sulfatase (STS), which converts inactive estrogen sulfates to active estrogens, may have contributed to the estrogen excess in chronic liver disease. METHODS: We performed bioinformatic analysis, real-time PCR, immunohistochemistry, and UPLC/MS-MS to analyze hepatic STS expression and serum estrogen levels in patients with chronic liver diseases. The crosstalk between NF-κB pathway and STS-regulated estrogen signaling was investigated by electrophoretic mobility shift assay, chromatin immunoprecipitation, luciferase assay and gene knockdown experiments in human hepatocytes. RESULTS: Hepatic STS was induced in patients with chronic inflammatory liver diseases, which was accompanied by increased circulating estrogen levels. The human STS gene, but not the mouse Sts gene, was induced by inflammatory stimuli in hepatic cells. Mechanistically, STS was established as a novel NF-κB target gene, whose induction facilitated the conversion of inactive estrogen sulfates to active estrogens, and consequently attenuated the inflammatory response. In contrast, genetic or pharmacological inhibition of STS or a direct blockade of estrogen signaling sensitized liver cells to the transcriptional activation of NF-κB and inflammatory response, possibly through the inhibition of IκB kinase activation. CONCLUSIONS: Our results suggest a negative feedback loop in chronic inflammatory liver diseases, in which the inflammatory activation of NF-κB induces STS gene expression. The induced STS facilitates the conversion of inactive estrogen sulfates to active estrogens, which in return attenuates the NF-κB-mediated inflammation.
BACKGROUND & AIMS: Chronic inflammatory liver diseases are associated with estrogen excess and feminization in men, which is thought to be due to compromised liver function to break down estrogens. The goal of this study is to determine whether the inflammatory induction of steroid sulfatase (STS), which converts inactive estrogen sulfates to active estrogens, may have contributed to the estrogen excess in chronic liver disease. METHODS: We performed bioinformatic analysis, real-time PCR, immunohistochemistry, and UPLC/MS-MS to analyze hepatic STS expression and serum estrogen levels in patients with chronic liver diseases. The crosstalk between NF-κB pathway and STS-regulated estrogen signaling was investigated by electrophoretic mobility shift assay, chromatin immunoprecipitation, luciferase assay and gene knockdown experiments in human hepatocytes. RESULTS: Hepatic STS was induced in patients with chronic inflammatory liver diseases, which was accompanied by increased circulating estrogen levels. The human STS gene, but not the mouse Sts gene, was induced by inflammatory stimuli in hepatic cells. Mechanistically, STS was established as a novel NF-κB target gene, whose induction facilitated the conversion of inactive estrogen sulfates to active estrogens, and consequently attenuated the inflammatory response. In contrast, genetic or pharmacological inhibition of STS or a direct blockade of estrogen signaling sensitized liver cells to the transcriptional activation of NF-κB and inflammatory response, possibly through the inhibition of IκB kinase activation. CONCLUSIONS: Our results suggest a negative feedback loop in chronic inflammatory liver diseases, in which the inflammatory activation of NF-κB induces STS gene expression. The induced STS facilitates the conversion of inactive estrogen sulfates to active estrogens, which in return attenuates the NF-κB-mediated inflammation.
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