Autocrine/paracrine regulation of the growth of the biliary tree by the neuroendocrine hormone serotonin.
OBJECTIVE
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.
Marzioni
Marco
M
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.
Glaser
Shannon
S
Francis
Heather
H
Marucci
Luca
L
Benedetti
Antonio
A
Alvaro
Domenico
D
Taffetani
Silvia
S
Ueno
Yoshiyuki
Y
Roskams
Tania
T
Phinizy
Jo Lynne
JL
Venter
Juliet
J
Fava
Giammarco
G
Lesage
Gene D
GD
Alpini
Gianfranco
G
D000818:Animals; D019898:Autocrine Communication / Q000502:physiology*; D001659:Biliary Tract / Q000166:cytology / Q000254:growth & development*; D018929:Cell Culture Techniques; D049109:Cell Proliferation; D002779:Cholestasis / Q000503:physiopathology; D002908:Chronic Disease; D008297:Male; D023421:Models, Animal; D009490:Neurosecretory Systems / Q000502:physiology; D019899:Paracrine Communication / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D044302:Receptor, Serotonin, 5-HT1B / Q000378:metabolism; D012701:Serotonin / Q000502:physiology*; D015398:Signal Transduction
D044302:Receptor, Serotonin, 5-HT1B; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin