Nervous and Neuroendocrine regulation of the pathophysiology of cholestasis and of biliary carcinogenesis

Table 1 Neuroendocrine hormones affecting cholangiocyte biology

Hormone	Receptor	Effect on cholangiocyte biology	Reference
Secretin	SR	Stimulates HCO3- secretion through the increase of cAMP/PKA and opening of CFTR	1, 34-43
Somatostatin	SSTR2	Counteracts the effect of secretin; stimulates bile absorption	44, 45
Insulin	IR	Counteracts the effect of secretin	46
ET-1	ETA-ETB	Counteracts the effect of secretin; reduces the SR expression	47
VIP	unspecified	Increases HCO3- and water secretion	48, 49
Bombesin	unspecified	Increases HCO3- and water secretion	50
Gastrin	CCK-B/gastrin	Counteracts the effect of secretin; reduces cell proliferation	40, 51
Estrogens	ERα-ERβ	Stimulate cell proliferation	52-55
Serotonin	5HT1A-5HT1B	Synthesized and secreted by cholangiocytes in the course of cholestasis. Counteracts the effect of secretin and reduces cell growth	58
GH/IGF-1	GH-R-IGF-1R	Stimulate cell proliferation	59

Table 2 Neurotransmitters/neurotrophins affecting cholangi-ocyte biology

Peptide	Receptor	Effect on cholangiocyte biology	Reference
Acetylcholine	M3	Potentiates the effect of secretin. Required for cholangiocyte response to BDL: sustains cholangiocyte proliferation and prevents apoptosis	43, 60, 61, 64, 65
Epinephrine/ Norephinephrine	α1	Potentiates the effect of secretin	67
Epinephrine/ Norephinephrine	β1-β2	Required for cholangiocyte response to BDL: sustains cholangiocyte proliferation and prevents apoptosis	70
Dopamine	D2	Inhibits secretin-induced ductal secretion	73
NGF	TrkA	Secreted by hyperplastic, cholestatic cholangiocytes; sustains the rpoliferative response to BDL	74

Table 3 Neuroendocrine hormones affecting cholangio-carcinoma cell biology

Hormone	Receptor	Effect on cholangiocarcinoma cell biology	Reference
Estrogens	ER	Stimulated SK-ChA-1 human cholangiocarcinoma cell growth	81
		Tamoxifen induced dose-dependent growth inhibition of OZ and SK-ChA-1 human cells in vitro; reduced growth of a SK-ChA-1 tumor cell xenografts implanted in athymic nude mice	81
		Tamoxifen stimulated SK-ChA-1 human cholangiocarcinoma apoptotic cell death	82
		Tamoxifen induced human cholangi-ocarcinoma cell apoptosis in vitro and inhibited tumor xenograft growth after pretreatment with IFN-gamma	83, 84
Gastrin	CCK-B/gastrin	Inhibited Mz-ChA-1, HuH-28, and TFK-1 human cell lines proliferation and induced Mz-ChA-1 cell apoptosis	90
CCK	CCK	Reduced the growth of SLU-132 human tumor xenografts implanted in nude mice; stimulated the release of carcinoembryonic antigen (CEA) by SLU-132 cells	93

Table 4 Neuroendocrine hormones affecting cholangio-carcinoma cell biology

Hormone	Receptor	Effect on cholangiocarcinoma cell biology	Reference
Somatostatin, analogues (octreotide, lanreotide)	SSTR2	Inhibited human cholangiocarcinoma cell proliferation in vitro and reduced human cholangiocarcinoma cell growth implanted in athymic mice	96
		Inhibited RBE, NEC, QBC939, and SSP-25 cell proliferation in vitro through cell cycle arrest and QBC939 xenografts growth	95
GABA	GABAA,-B,-C	Inhibited human Mz-ChA-1, HuH-28 and TFK-1 cell proliferation in vitro; reduced malignant cholangiocyte migration. Reduced Mz-ChA-1 xenograft tumor growth implanted in athymic mice	98
NPY	NPY-Y5	Inhibited Mz-ChA-1 cell proliferation in vitro	99

Table 5 Neurotransmitters/neurotrophins affecting cholangiocarcinoma cell biology

Peptide	Receptor	Effect on cholangiocarcinomacell biology	Reference
Epinephrine/ Norephinephrine	α2	UK 14,304 inhibited human Mz-ChA-1 and TFK-1 cell proliferation in vitro	[80]
Acetylcholine	M1	Carbachol produced an increase of IP3 and Ca2+ intracellular levels in Mz-ChA-1 cells	[62]