Konstantina Kyritsi1, Lixian Chen2, April O'Brien2, Heather Francis1,3, Travis W Hein2, Julie Venter1, Nan Wu1, Ludovica Ceci1, Tianhao Zhou2, David Zawieja2, Anatoliy A Gashev2, Fanyin Meng1,3, Pietro Invernizzi4,5, Luca Fabris6,7, Chaodong Wu8, Nicholas J Skill9, Romil Saxena10, Suthat Liangpunsakul1,3, Gianfranco Alpini1,3, Shannon S Glaser2. 1. Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN. 2. Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX. 3. Indiana University School of Medicine, Research, Richard L. Roudebush VA Medical Center, Indianapolis, IN. 4. Humanitas Clinical and Research Center, Rozzano (MI), Italy. 5. Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA. 6. Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy. 7. Digestive Disease Section, Yale University School of Medicine, New Haven, CT. 8. Department of Nutrition and Food Science, Texas A&M University, College Station, TX. 9. Department of Surgery, Indiana University School of Medicine, Indianapolis, IN. 10. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN.
Abstract
BACKGROUND AND AIMS: Serotonin (5HT) is a neuroendocrine hormone synthetized in the central nervous system (CNS) as well as enterochromaffin cells of the gastrointestinal tract. Tryptophan hydroxylase (TPH1) and monoamine oxidase (MAO-A) are the key enzymes for the synthesis and catabolism of 5HT, respectively. Previous studies demonstrated that 5-hydroxytryptamine receptor (5HTR)1A/1B receptor agonists inhibit biliary hyperplasia in bile-duct ligated (BDL) rats, whereas 5HTR2B receptor antagonists attenuate liver fibrosis (LF) in mice. Our aim was to evaluate the role of 5HTR2A/2B/2C agonists/antagonists in cholestatic models. APPROACH AND RESULTS: While in vivo studies were performed in BDL rats and the multidrug resistance gene 2 knockout (Mdr2-/- ) mouse model of PSC, in vitro studies were performed in cell lines of cholangiocytes and hepatic stellate cells (HSCs). 5HTR2A/2B/2C and MAO-A/TPH1 are expressed in cholangiocytes and HSCs from BDL rats and Mdr2-/- - mice. Ductular reaction, LF, as well as the mRNA expression of proinflammatory genes increased in normal, BDL rats, and Mdr2-/- - mice following treatment 5HTR2A/2B/2C agonists, but decreased when BDL rats and Mdr2-/- mice were treated with 5HTR2A/2B/2C antagonists compared to BDL rats and Mdr2-/- mice, respectively. 5HT levels increase in Mdr2-/- mice and in PSC human patients compared to their controls and decrease in serum of Mdr2-/- mice treated with 5HTR2A/2B/2C antagonists compared to untreated Mdr2-/- mice. In vitro, cell lines of murine cholangiocytes and human HSCs express 5HTR2A/2B/2C and MAO-A/TPH1; treatment of these cell lines with 5HTR2A/2B/2C antagonists or TPH1 inhibitor decreased 5HT levels as well as expression of fibrosis and inflammation genes compared to controls. CONCLUSIONS: Modulation of the TPH1/MAO-A/5HT/5HTR2A/2B/2C axis may represent a therapeutic approach for management of cholangiopathies, including PSC.
BACKGROUND AND AIMS: Serotonin (5HT) is a neuroendocrine hormone synthetized in the central nervous system (CNS) as well as enterochromaffin cells of the gastrointestinal tract. Tryptophan hydroxylase (TPH1) and monoamine oxidase (MAO-A) are the key enzymes for the synthesis and catabolism of 5HT, respectively. Previous studies demonstrated that 5-hydroxytryptamine receptor (5HTR)1A/1B receptor agonists inhibit biliary hyperplasia in bile-duct ligated (BDL) rats, whereas 5HTR2B receptor antagonists attenuate liver fibrosis (LF) in mice. Our aim was to evaluate the role of 5HTR2A/2B/2C agonists/antagonists in cholestatic models. APPROACH AND RESULTS: While in vivo studies were performed in BDL rats and the multidrug resistance gene 2 knockout (Mdr2-/- ) mouse model of PSC, in vitro studies were performed in cell lines of cholangiocytes and hepatic stellate cells (HSCs). 5HTR2A/2B/2C and MAO-A/TPH1 are expressed in cholangiocytes and HSCs from BDL rats and Mdr2-/- - mice. Ductular reaction, LF, as well as the mRNA expression of proinflammatory genes increased in normal, BDL rats, and Mdr2-/- - mice following treatment 5HTR2A/2B/2C agonists, but decreased when BDL rats and Mdr2-/- mice were treated with 5HTR2A/2B/2C antagonists compared to BDL rats and Mdr2-/- mice, respectively. 5HT levels increase in Mdr2-/- mice and in PSChumanpatients compared to their controls and decrease in serum of Mdr2-/- mice treated with 5HTR2A/2B/2C antagonists compared to untreated Mdr2-/- mice. In vitro, cell lines of murine cholangiocytes and human HSCs express 5HTR2A/2B/2C and MAO-A/TPH1; treatment of these cell lines with 5HTR2A/2B/2C antagonists or TPH1 inhibitor decreased 5HT levels as well as expression of fibrosis and inflammation genes compared to controls. CONCLUSIONS: Modulation of the TPH1/MAO-A/5HT/5HTR2A/2B/2C axis may represent a therapeutic approach for management of cholangiopathies, including PSC.
Authors: Dong Chan Kim; Dae Won Jun; Young Il Kwon; Kang Nyeong Lee; Hang Lak Lee; Oh Young Lee; Byung Chul Yoon; Ho Soon Choi; Eun Kyung Kim Journal: Liver Int Date: 2013-01-31 Impact factor: 5.828
Authors: Wiebke Janssen; Yves Schymura; Tatyana Novoyatleva; Baktybek Kojonazarov; Mario Boehm; Astrid Wietelmann; Himal Luitel; Kirsten Murmann; Damian Richard Krompiec; Aleksandra Tretyn; Soni Savai Pullamsetti; Norbert Weissmann; Werner Seeger; Hossein Ardeschir Ghofrani; Ralph Theo Schermuly Journal: Biomed Res Int Date: 2015-02-01 Impact factor: 3.411