title: Bile acids evoke placental inflammation by activating Gpbar1/NF-κB pathway in intrahepatic cholestasis of pregnancy.
abstract: Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic disorder with potentially deleterious consequences for fetuses. Although a clear correlation between the elevated levels of maternal serum bile acids and deficient fetal outcome has been established in clinical practice, the underlying mechanisms remain elusive. Herein, we report that bile acids induce NF-κB pathway activation via G protein-coupled bile acid receptor 1 (Gpbar1), with consequent upregulation of inflammatory genes in trophoblasts, leading to aberrant leukocyte infiltration and inflammation in placenta. Ursodeoxycholic acid (UDCA), a drug used clinically to treat ICP, competes with other bile acids for binding with Gpbar1 and thus inhibits bile acid-induced inflammatory response in trophoblasts and improves fetal survival in pregnant rats with obstructive cholestasis. Notably, inhibition of NF-κB by andrographolide is more effective than UDCA in benefiting placentas and fetuses. Thus, anti-inflammation therapy targeting Gpbar1/NF-κB pathway could be effective in suppressing bile acid-induced inflammation and alleviating ICP-associated fetal disorders.
authors.affiliation: State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: YouHua
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: YouDong
authors.initials: Y
authors.lastname: Pan
authors.affiliation: State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: ChangDong
authors.initials: C
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: YaJuan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: HaiLong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: JunLei
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: MengYa
authors.initials: M
authors.lastname: Yuan
authors.affiliation: Department of Obstetrics, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 200040, China jfchen@sibcb.ac.cn qldu2004@126.com tduan@yahoo.com.
authors.forename: Tao
authors.initials: T
authors.lastname: Duan
authors.affiliation: Department of Obstetrics, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 200040, China jfchen@sibcb.ac.cn qldu2004@126.com tduan@yahoo.com.
authors.forename: QiaoLing
authors.initials: Q
authors.lastname: Du
authors.affiliation: State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China jfchen@sibcb.ac.cn qldu2004@126.com tduan@yahoo.com.
authors.forename: JianFeng
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000009:adverse effects*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002780:Cholestasis, Intrahepatic / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D004224:Diterpenes / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology*; D007962:Leukocytes / Q000187:drug effects / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010920:Placenta / Q000473:pathology*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011256:Pregnancy Outcome; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014327:Trophoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014580:Ursodeoxycholic Acid / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D001647:Bile Acids and Salts; D004224:Diterpenes; C473772:GPBAR1 protein, human; D016328:NF-kappa B; D043562:Receptors, G-Protein-Coupled; C030419:andrographolide; D014580:Ursodeoxycholic Acid; D019869:Phosphatidylinositol 3-Kinases
keywords: G protein-coupled receptor; fetal outcome; maternal cholestasis; placental inflammation; ursodeoxycholic acid