Progesterone stimulates the proliferation of female and male cholangiocytes via autocrine/paracrine mechanisms

Abstract

During cholestatic liver diseases, cholangiocytes express neuroendocrine phenotypes and respond to a number of hormones and neuropeptides by paracrine and autocrine mechanisms. We examined whether the neuroendocrine hormone progesterone is produced by and targeted to cholangiocytes, thereby regulating biliary proliferation during cholestasis. Nuclear (PR-A and PR-B) and membrane (PRGMC1, PRGMC2, and mPRα) progesterone receptor expression was evaluated in liver sections and cholangiocytes from normal and bile duct ligation (BDL) rats, and NRC cells (normal rat cholangiocyte line). In vivo, normal rats were chronically treated with progesterone for 1 wk, or immediately after BDL, rats were treated with a neutralizing progesterone antibody for 1 wk. Cholangiocyte growth was measured by evaluating the number of bile ducts in liver sections. The expression of the progesterone synthesis pathway was evaluated in liver sections, cholangiocytes and NRC. Progesterone secretion was evaluated in supernatants from normal and BDL cholangiocytes and NRC. In vitro, NRC were stimulated with progesterone and cholangiocyte supernatants in the presence or absence of antiprogesterone antibody. Aminoglutethimide was used to block progesterone synthesis. Cholangiocytes and NRC express the PR-B nuclear receptor and PRGMC1, PRGMC2, and mPRα. In vivo, progesterone increased the number of bile ducts of normal rats, whereas antiprogesterone antibody inhibited cholangiocyte growth stimulated by BDL. Normal and BDL cholangiocytes expressed the biosynthetic pathway for and secrete progesterone. In vitro, 1) progesterone increased NRC proliferation; 2) cholangiocyte supernatants increased NRC proliferation, which was partially inhibited by preincubation with antiprogesterone; and 3) inhibition of progesterone steroidogenesis prevented NRC proliferation. In conclusion, progesterone may be an important autocrine/paracrine regulator of cholangiocyte proliferation.

Involvement of cholangiocyte proliferation in biliary fibrosis

“…The nature of these cells, that is, whether they are fibroblasts, endothelial cells, transformed hepatocytes, or biliary ductules, is a subject of debate [6] . One of the functional characteristics of proliferating cholangiocytes is that they acquire a neuroendocrine phenotype, especially in "atypical" ductular reaction [9,32,34,35] . Proliferating cholangiocytes, from "atypical" proliferation, show phenotypical features of neuroendocrine cells like chromogranin A, S-100 protein glycolipid A2-B4, and a neural cell adhesion molecule [9] .…”

“…Proliferating cholangiocytes, from "atypical" proliferation, show phenotypical features of neuroendocrine cells like chromogranin A, S-100 protein glycolipid A2-B4, and a neural cell adhesion molecule [9] . During cholestatic liver diseases, the cholangiocytes express neuroendocrine phenotypes and respond to a number of hormones and neuropeptides [34] . For example, these proliferating cholangiocytes have increased expression and secretion of serotonin, endogenous opioid peptides and neurothrophins (and their corresponding receptors) [25] .…”

Follicle-stimulating hormone increases cholangiocyte proliferation by an autocrine mechanism via cAMP-dependent phosphorylation of ERK1/2 and Elk-1

“…Cholangiocyte hyperplasia is regulated by a number of factors including gastrointestinal hormones (24,46), cyclic adenosine 3Ј,5Ј-monophosphate (cAMP) (20), angiogenic growth factors [e.g., vascular endothelial growth factor (VEGF)] (17,21) and sex hormones such as estrogens (8), prolactin (58), and progesterone (25). The cAMP/ERK1/2/Elk-1 signaling has been shown to play a key role in the regulation of cholangiocyte proliferation (18,20,24,27,37).…”

“…Whether the FSH receptor is also linked to G␣ i has not yet been completely defined. In fact, the treatment of Sertoli cells with pertussis toxin (PTX, a G␣ i inhibitor) (29), an agent capable of removing the tonic inhibitory effects of G␣ i , increases FSH-induced aromatase activity, suggesting that the inhibitory activity of G␣ i may negatively modulate the PKA pathway of signal transduction (30).Studies have demonstrated the role of sex hormones in the regulation of the growth of the biliary epithelium (8,9,25,58). For example, in concert with growth factors, estrogens sustain cholangiocyte proliferation and reduce cholangiocyte apopto-…”

The Rats Liver External Secretory Function in Blockade of Androgen Receptors With Flutamide

“…Відомо, що гормони репродуктивної системи -естрогени, пролактин, фолітропін, прогесте-рон -чинять суттєвий вплив на холангіоцити, утворення та секрецію жовчі [1][2][3]. Ймовірна участь тестостерону у цих процесах підтвер-джується наявністю рецепторів андрогенів у гепатоцитах і холангіоцитах [4][5][6].…”