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Nat Commun. 2015 Aug 10;6:7979. doi: 10.1038/ncomms8979.

Oestrogen sulfotransferase ablation sensitizes mice to sepsis.

Author information

1
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.
2
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.
3
Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
4
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.
5
Surgical Research, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania 15240, USA.
6
1] Surgical Research, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania 15240, USA [2] Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
7
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
8
Department of Nutrition and Department of Environmental Toxicology, University of California, Davis, California 95616, USA.
9
Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
10
Institute of Clinical Pharmacology, Sun Yat-Sen University, Guangzhou, Guangdong 510006, China.
11
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.
12
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.

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.

PMID:
26259151
PMCID:
PMC4532951
DOI:
10.1038/ncomms8979
[Indexed for MEDLINE]
Free PMC Article

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