title: Histamine stimulates the proliferation of small and large cholangiocytes by activation of both IP3/Ca2+ and cAMP-dependent signaling mechanisms.
abstract: Although large cholangiocytes exert their functions by activation of cyclic adenosine 3',5'-monophosphate (cAMP), Ca(2+)-dependent signaling regulates the function of small cholangiocytes. Histamine interacts with four receptors, H1-H4HRs. H1HR acts by Gαq activating IP(3)/Ca(2+), whereas H2HR activates Gα(s) stimulating cAMP. We hypothesize that histamine increases biliary growth by activating H1HR on small and H2HR on large cholangiocytes. The expression of H1-H4HRs was evaluated in liver sections, isolated and cultured (normal rat intrahepatic cholangiocyte culture (NRIC)) cholangiocytes. In vivo, normal rats were treated with histamine or H1-H4HR agonists for 1 week. We evaluated: (1) intrahepatic bile duct mass (IBDM); (2) the effects of histamine, H1HR or H2HR agonists on NRIC proliferation, IP(3) and cAMP levels and PKCα and protein kinase A (PKA) phosphorylation; and (3) PKCα silencing on H1HR-stimulated NRIC proliferation. Small and large cholangiocytes express H1-H4HRs. Histamine and the H1HR agonist increased small IBDM, whereas histamine and the H2HR agonist increased large IBDM. H1HR agonists stimulated IP(3) levels, as well as PKCα phosphorylation and NRIC proliferation, whereas H2HR agonists increased cAMP levels, as well as PKA phosphorylation and NRIC proliferation. The H1HR agonist did not increase proliferation in PKCα siRNA-transfected NRICs. The activation of differential signaling mechanisms targeting small and large cholangiocytes is important for repopulation of the biliary epithelium during pathologies affecting different-sized bile ducts.
authors: Department of Internal Medicine, Scott and White Digestive Disease Research Center, Scott and White Hospital and Texas A&M Health Science Center, College of Medicine, Temple, TX, USA.
authors: Heather L
authors: HL
authors: Francis
authors: Sharon
authors: S
authors: Demorrow
authors: Antonio
authors: A
authors: Franchitto
authors: Julie K
authors: JK
authors: Venter
authors: Romina A
authors: RA
authors: Mancinelli
authors: Mellanie A
authors: MA
authors: White
authors: Fanyin
authors: F
authors: Meng
authors: Yoshiyuki
authors: Y
authors: Ueno
authors: Guido
authors: G
authors: Carpino
authors: Anastasia
authors: A
authors: Renzi
authors: Kimberly K
authors: KK
authors: Baker
authors: Hannah E
authors: HE
authors: Shine
authors: Taylor C
authors: TC
authors: Francis
authors: Eugenio
authors: E
authors: Gaudio
authors: Gianfranco D
authors: GD
authors: Alpini
authors: Paolo
authors: P
authors: Onori
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006632:Histamine / Q000494:pharmacology*; D007295:Inositol Phosphates / Q000378:metabolism*; D008297:Male; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D007295:Inositol Phosphates; D006632:Histamine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D051571:Protein Kinase C-alpha; D002118:Calcium