Progesterone stimulates the proliferation of female and male cholangiocytes via autocrine/paracrine mechanisms.
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 mPRalpha) 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 mPRalpha. 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.
Department of Medicine, Scott & White Hospital and Texas A&M University System Health Science Center, College of Medicine, Temple, Texas 76504, USA. sglaser@tamu.edu
Shannon
S
Glaser
Sharon
S
DeMorrow
Heather
H
Francis
Yoshiyuki
Y
Ueno
Eugenio
E
Gaudio
Shelley
S
Vaculin
Julie
J
Venter
Antonio
A
Franchitto
Paolo
P
Onori
Bradley
B
Vaculin
Marco
M
Marzioni
Candace
C
Wise
Metaneeya
M
Pilanthananond
Jennifer
J
Savage
Lisa
L
Pierce
Romina
R
Mancinelli
Gianfranco
G
Alpini
D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019898:Autocrine Communication / Q000502:physiology*; D001652:Bile Ducts / Q000166:cytology* / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D008297:Male; D019899:Paracrine Communication / Q000502:physiology*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011374:Progesterone / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D012727:Sex Characteristics; D000098682:Steroidogenic Acute Regulatory Protein
D010750:Phosphoproteins; D011980:Receptors, Progesterone; D000098682:Steroidogenic Acute Regulatory Protein; D011374:Progesterone; D003577:Cytochrome P-450 Enzyme System; D015096:3-Hydroxysteroid Dehydrogenases