title: Oestrogen sulfotransferase ablation sensitizes mice to sepsis.
abstract: Sepsis is the host's deleterious systemic inflammatory response to microbial infections. Here we report an essential role for the oestrogen sulfotransferase (EST or SULT1E1), a conjugating enzyme that sulfonates and deactivates estrogens, in sepsis response. Both the caecal ligation and puncture (CLP) and lipopolysaccharide models of sepsis induce the expression of EST and compromise the activity of oestrogen, an anti-inflammatory hormone. Surprisingly, EST ablation sensitizes mice to sepsis-induced death. Mechanistically, EST ablation attenuates sepsis-induced inflammatory responses due to compromised oestrogen deactivation, leading to increased sepsis lethality. In contrast, transgenic overexpression of EST promotes oestrogen deactivation and sensitizes mice to CLP-induced inflammatory response. The induction of EST by sepsis is NF-κB dependent and EST is a NF-κB-target gene. The reciprocal regulation of inflammation and EST may represent a yet-to-be-explored mechanism of endocrine regulation of inflammation, which has an impact on the clinical outcome of sepsis.
authors.affiliation: 1] Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA [2] Department of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Chai
authors.affiliation: 1] Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA [2] Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Mengxi
authors.initials: M
authors.lastname: Jiang
authors.affiliation: 1] Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA [2] Institute of Clinical Pharmacology, Sun Yat-Sen University, Guangzhou, Guangdong 510006, China.
authors.forename: Bingfang
authors.initials: B
authors.lastname: Hu
authors.affiliation: Surgical Research, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania 15240, USA.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Li
authors.affiliation: 1] Surgical Research, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania 15240, USA [2] Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Meihong
authors.initials: M
authors.lastname: Deng
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.affiliation: Department of Nutrition and Department of Environmental Toxicology, University of California, Davis, California 95616, USA.
authors.forename: Heidi R
authors.initials: HR
authors.lastname: Kucera
authors.affiliation: Department of Nutrition and Department of Environmental Toxicology, University of California, Davis, California 95616, USA.
authors.forename: Nilesh W
authors.initials: NW
authors.lastname: Gaikwad
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Meishu
authors.initials: M
authors.lastname: Xu
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Peipei
authors.initials: P
authors.lastname: Lu
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Jiong
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Fu
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Youhua
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 1] Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA [2] Department of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Lushan
authors.initials: L
authors.lastname: Yu
authors.affiliation: Institute of Clinical Pharmacology, Sun Yat-Sen University, Guangzhou, Guangdong 510006, China.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Su
authors.initials: S
authors.lastname: Zeng
authors.affiliation: 1] Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA [2] Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Xie
mesh_terms: D000818:Animals; D002432:Cecum / Q000473:pathology; D004967:Estrogens / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D020022:Genetic Predisposition to Disease; D056945:Hep G2 Cells; D006801:Humans; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018805:Sepsis / Q000235:genetics*; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D014599:Uterus / Q000187:drug effects
chemical_list: D004967:Estrogens; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D015238:Sulfotransferases; C020122:estrone sulfotransferase