title: Melatonin inhibits cholangiocyte hyperplasia in cholestatic rats by interaction with MT1 but not MT2 melatonin receptors.
abstract: In bile duct-ligated (BDL) rats, large cholangiocytes proliferate by activation of cAMP-dependent signaling. Melatonin, which is secreted from pineal gland as well as extrapineal tissues, regulates cell mitosis by interacting with melatonin receptors (MT1 and MT2) modulating cAMP and clock genes. In the liver, melatonin suppresses oxidative damage and ameliorates fibrosis. No information exists regarding the role of melatonin in the regulation of biliary hyperplasia. We evaluated the mechanisms of action by which melatonin regulates the growth of cholangiocytes. In normal and BDL rats, we determined the hepatic distribution of MT1, MT2, and the clock genes, CLOCK, BMAL1, CRY1, and PER1. Normal and BDL (immediately after BDL) rats were treated in vivo with melatonin before evaluating 1) serum levels of melatonin, bilirubin, and transaminases; 2) intrahepatic bile duct mass (IBDM) in liver sections; and 3) the expression of MT1 and MT2, clock genes, and PKA phosphorylation. In vitro, large cholangiocytes were stimulated with melatonin in the absence/presence of luzindole (MT1/MT2 antagonist) and 4-phenyl-2-propionamidotetralin (MT2 antagonist) before evaluating cell proliferation, cAMP levels, and PKA phosphorylation. Cholangiocytes express MT1 and MT2, CLOCK, BMAL1, CRY1, and PER1 that were all upregulated following BDL. Administration of melatonin to BDL rats decreased IBDM, serum bilirubin and transaminases levels, the expression of all clock genes, cAMP levels, and PKA phosphorylation in cholangiocytes. In vitro, melatonin decreased the proliferation, cAMP levels, and PKA phosphorylation, decreases that were blocked by luzindole. Melatonin may be important in the management of biliary hyperplasia in human cholangiopathies.
authors.affiliation: Temple, TX 76504, USA. galpini@tamu.edu
authors.forename: Anastasia
authors.initials: A
authors.lastname: Renzi
authors.forename: Shannon
authors.initials: S
authors.lastname: Glaser
authors.forename: Sharon
authors.initials: S
authors.lastname: Demorrow
authors.forename: Romina
authors.initials: R
authors.lastname: Mancinelli
authors.forename: Fanyin
authors.initials: F
authors.lastname: Meng
authors.forename: Antonio
authors.initials: A
authors.lastname: Franchitto
authors.forename: Julie
authors.initials: J
authors.lastname: Venter
authors.forename: Mellanie
authors.initials: M
authors.lastname: White
authors.forename: Heather
authors.initials: H
authors.lastname: Francis
authors.forename: Yuyan
authors.initials: Y
authors.lastname: Han
authors.forename: Domenico
authors.initials: D
authors.lastname: Alvaro
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
authors.forename: Guido
authors.initials: G
authors.lastname: Carpino
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ueno
authors.forename: Paolo
authors.initials: P
authors.lastname: Onori
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Alpini
mesh_terms: D056930:ARNTL Transcription Factors / Q000096:biosynthesis; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D001652:Bile Ducts / Q000166:cytology / Q000473:pathology*; D056926:CLOCK Proteins / Q000096:biosynthesis; D049109:Cell Proliferation / Q000187:drug effects; D002779:Cholestasis / Q000473:pathology; D056931:Cryptochromes / Q000096:biosynthesis; D000242:Cyclic AMP / Q000378:metabolism; D006965:Hyperplasia / Q000188:drug therapy / Q000473:pathology; D008026:Ligation; D008297:Male; D008550:Melatonin / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D056950:Period Circadian Proteins / Q000096:biosynthesis; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D044122:Receptor, Melatonin, MT1 / Q000096:biosynthesis / Q000187:drug effects* / Q000378:metabolism; D044123:Receptor, Melatonin, MT2 / Q000096:biosynthesis / Q000378:metabolism; D012633:Secretin / Q000494:pharmacology
chemical_list: D056930:ARNTL Transcription Factors; D001639:Bicarbonates; C538964:Cry1 protein, mouse; D056931:Cryptochromes; C539023:Per1 protein, mouse; D056950:Period Circadian Proteins; D018809:Proliferating Cell Nuclear Antigen; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D012633:Secretin; D000242:Cyclic AMP; D056926:CLOCK Proteins; C538944:Clock protein, mouse; D008550:Melatonin