Abstract | BACKGROUND & AIMS: METHODS: The expression of neurotrophins and their receptors was investigated by immunohistochemistry in liver sections and reverse-transcription polymerase chain reaction and immunoblots in isolated cholangiocytes. In vitro, the effect of NGF on cholangiocyte proliferation and signal transduction was investigated by immunoblotting for proliferating cell nuclear antigen, phosphorylated AKT (p-AKT), phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), phosphorylated c-jun-N-terminal kinase, and phosphorylated p38. In vivo, rats that had undergone bile duct ligation (BDL) were treated with an anti- NGF antibody to immunoneutralize NGF and bile duct mass, proliferation, apoptosis, and inflammation were investigated by immunohistochemistry. RESULTS:
NGF and its TrkA receptor were expressed by normal rat cholangiocytes and up-regulated following BDL. Cholangiocytes secrete NGF, and secretion is increased in proliferating BDL cholangiocytes. In vitro, NGF stimulated cholangiocyte proliferation, which was associated with enhanced p-AKT and p-ERK1/2 expression. NGF proliferation in vitro was partially blocked by the MEK inhibitor ( UO126) and completely ablated by the phosphatidylinositol 3-kinase inhibitor ( wortmannin). In vitro, NGF and estrogens have an additive effect on cholangiocyte proliferation by acting on phosphorylated TrkA and p-ERK1/2. In vivo, immunoneutralization of NGF decreased bile duct mass in BDL rats, which was associated with depressed proliferation and enhanced apoptosis and with increased portal inflammation. CONCLUSIONS:
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Authors | Alessandro Gigliozzi, Gianfranco Alpini, Gianluca Svegliati Baroni, Luca Marucci, Veronica Drudi Metalli, Shannon S Glaser, Heather Francis, Maria Grazia Mancino, Yoshiyuki Ueno, Barbara Barbaro, Antonio Benedetti, Adolfo F Attili, Domenico Alvaro |
Journal | Gastroenterology
(Gastroenterology)
Vol. 127
Issue 4
Pg. 1198-209
(Oct 2004)
ISSN: 0016-5085 [Print] United States |
PMID | 15480997
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Estradiol
- Nerve Growth Factor
- Phosphatidylinositol 3-Kinases
- Receptor, trkA
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Topics |
- Animals
- Bile Ducts, Intrahepatic
(cytology)
- Cell Division
- Cholestasis
(pathology)
- Epithelial Cells
(cytology)
- Estradiol
(pharmacology)
- Immunohistochemistry
- MAP Kinase Signaling System
- Male
- Nerve Growth Factor
(physiology)
- Phosphatidylinositol 3-Kinases
(physiology)
- Rats
- Rats, Inbred F344
- Receptor, trkA
(physiology)
- Reverse Transcriptase Polymerase Chain Reaction
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