Table 2.
Peptide Hormones and Other Neuroendocrine Factors That Affect Cholangiocyte Proliferation and Function
| Hormone | Receptors | Effect on proliferation | References |
|---|---|---|---|
| CGRP (α/β) | CLR, RAMP1, RCP | Stimulates an increase in biliary mass; lack of CGRP reduces biliary proliferation in response to BDL | 27 |
| Estrogen | ER-α/ER-β | Stimulates cholangiocyte proliferation | 28–31 |
| Gastrin | CCK-B/gastrin | Counteracts the effect of secretin; inhibits cholangiocyte proliferation during BDL | 32,33 |
| GH/IGF-1 | GH-R/IGF1R | Stimulates cholangiocyte proliferation; GH stimulates production and release of IGF-1 that modulates cell proliferation | 34 |
| GLP-1 (exendin-4) | GLP-1R | GLP-1 is expressed by cholestatic cholangiocytes; stimulates biliary proliferation; exendin-4 protects cholangiocytes from apoptosis | 35,36 |
| NGF | TrkA | Secreted by cholestatic cholangiocytes; supports the proliferative response to BDL | 37 |
| Progesterone | PR-A/B; mPR | Stimulates proliferation in normal and cholestatic cholangiocytes via autocrine/paracrine mechanisms | 38 |
| Secretin | SR | Stimulates proliferation of normal and cholestatic cholangiocytes; lack of SR reduces biliary hyperplasia in response to BDL | 39 |
| Somatostatin | SSTR2 | Counteracts the effect of secretin-stimulated biliary secretion; inhibits proliferation | 40–42 |
| VEGF | VEGR2 and 3 | Secreted by cholangiocytes during cholestasis and stimulates an increase in biliary proliferation; prevents cholangiocyte apoptosis induced by interruption of the blood flow of the hepatic artery; VEGF receptor inhibitor, SU-5416, blocked liver cyst growth in Pkd2WS25/– mice | 43–46 |
| ET-1 | ETA and ETB | ET-1 inhibits secretin-induced ductal secretion | 47 |
| Cytokines (IL-6, IL-8) | gp130 CXCR2 | CXCR2 agonists in ADPKD liver cyst fluids promote cholangiocyte proliferation; IL-6 and IL-8 are secreted by cholangiocytes | 48 |
| Prolactin | Prolactin receptor (short and long) | Stimulates the proliferation of normal female cholangiocytes by differential regulation of Ca2+-dependent PKC isoforms | 49,50 |
| FSH | FSH receptor | Induces biliary hyperplasia via an autocrine mechanism by the activation of cAMP-dependent ERK1/2 and Elk-1 | 51 |
CLR, calcitonin receptor-like receptor; Elk-1, ets-like gene-1; GH, growth hormone; IL-6, interleukin-6; RAMP1, receptor activity-modifying protein 1; RCP, receptor component protein; TrkA, neurotrophic tyrosine kinase receptor type 1.