Autocrine/paracrine regulation of the growth of the biliary tree by the neuroendocrine hormone serotonin
Authors: Gene D Lesage
Marco Marzioni
Giammarco Fava
Antonio Benedetti
Shannon Glaser
Jo Lynne Phinizy
Domenico Alvaro
Gianfranco Alpini
Tania Roskams
Heather Francis
Silvia Taffetani
Luca Marucci
Yoshiyuki Ueno
Juliet Venter
Journal: Gastroenterology (2005)
Discipline: CLINICAL MEDICINE
Keywords: biliary tree; cholangiopathies; cholangiocytes; serotonin; proliferation
Affiliations: Department of Medical Physiology, Scott & White Hospital, and Texas A&M University Health System Science Center, 702 Southwest H.K. Dodgen Loop, Temple, TX 76504, USA.

Abstract:  Background &amp; aims: The biliary tree is the target of cholangiopathies that are chronic cholestatic liver diseases characterized by loss of proliferative response and enhanced apoptosis of cholangiocytes, the epithelial cells lining the biliary tree. The endogenous factors that regulate cholangiocyte proliferation are poorly understood. Therefore, we studied the role of the neuroendocrine hormone serotonin as a modulator of cholangiocyte proliferation. Methods: The presence of the serotonin 1A and 1B receptors on cholangiocytes was evaluated. We then tested whether the activation of such receptors by the administration of the selective agonists modifies cholangiocyte proliferation and functional activity both in vivo and in vitro. In addition, the intracellular signal mediating the serotonin receptor action in cholangiocytes was characterized. We studied the expression and secretion of serotonin by cholangiocytes and the effects of the neutralization of the secreted hormone on the growth of the biliary tree. Results: Cholangiocytes express the serotonin 1A and 1B receptors. Their activation markedly inhibits the growth and choleretic activity of the biliary tree in the bile duct-ligated rat, a model of chronic cholestasis. Such changes are mediated by enhanced d -myo-inositol 1,4,5-triphosphate/Ca 2+ /protein kinase C signaling and the consequent inhibition of the adenosine 3',5'-cyclic monophosphate/protein kinase A/Src/extracellular signal-regulated kinase 1/2 cascade. Cholangiocytes secrete serotonin, the blockage of which enhances cholangiocyte proliferation in the course of cholestasis. Conclusions: We observed the existence of an autocrine loop based on serotonin that limits the growth of the biliary tree in the course of chronic cholestasis. Our novel findings might open new approaches for the management of cholangiopathies. 

Retracted: No

PubPeer comments:
 The same beta actin has been reproduced three times in Figure 5 (Panel A and B). Can the authors explain ![file] , 
 Figure 5. Total -Src appears to be the same in the two images shown in Panel A. Could the authors provide the uncropped scans used to prepare these figures? ![file] , 
 Figure 5 of this paper Gastroenterology 2005- 10.1053 j.gastro.2004.10.002 is duplicated from Figure 4 of a previsous paper by some of the same authors : Am J Physiol Gastrointest Liver Physiol 284: G837u2013G852, 2003. First published January 29, 2003; 10.1152 ajpgi.00398.2002. The same image was used to indicate total AKT in the AJP 2003 and Beta-actin in Gastroenterology 2005. ![file] , 
 Images duplicated in three papers by benedetti et al. The same images were used to indicate total AKT (2003 and 2007) and beta actin (2005). Some of the images were flipped horizontally. None of the  densitometric analyses shown in these figures correspond to a real experiment. ![file] ![file] ,