title: Inflammatory regulation of steroid sulfatase: A novel mechanism to control estrogen homeostasis and inflammation in chronic liver disease.
abstract: OBJECTIVE
  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.
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Mengxi
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tuebingen, Tuebingen, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Klein
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tuebingen, Tuebingen, Germany.
authors.forename: Ulrich M
authors.initials: UM
authors.lastname: Zanger
authors.affiliation: Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine Louisville, KY, USA.
authors.forename: Mohammad K
authors.initials: MK
authors.lastname: Mohammad
authors.affiliation: Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine Louisville, KY, USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Cave
authors.affiliation: Department of Nutrition and Department of Environmental Toxicology, University of California, Davis, CA, USA.
authors.forename: Nilesh W
authors.initials: NW
authors.lastname: Gaikwad
authors.affiliation: Department of Biological Sciences, Duquesne University, Pittsburgh, PA, USA.
authors.forename: Natasha J
authors.initials: NJ
authors.lastname: Dias
authors.affiliation: Department of Biological Sciences, Duquesne University, Pittsburgh, PA, USA.
authors.forename: Kyle W
authors.initials: KW
authors.lastname: Selcer
authors.affiliation: 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.
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Jinhan
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Xiuhui
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Qiujin
authors.initials: Q
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Qin
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Li
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Wen
authors.initials: W
authors.lastname: Xie
mesh_terms: D002478:Cells, Cultured; D002908:Chronic Disease; D019295:Computational Biology; D004967:Estrogens / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007249:Inflammation / Q000209:etiology*; D008104:Liver Cirrhosis, Alcoholic / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism*; D016328:NF-kappa B / Q000502:physiology; D015398:Signal Transduction; D043266:Steryl-Sulfatase / Q000502:physiology*
chemical_list: D004967:Estrogens; D016328:NF-kappa B; C584039:STS protein, human; D043266:Steryl-Sulfatase
keywords: Estrogen metabolism; Estrogens; Inflammation; Liver disease; Steroid sulfatase