cAMP stimulates the secretory and proliferative capacity of the rat intrahepatic biliary epithelium through changes in the PKA/Src/MEK/ERK1/2 pathway
| Autor: | Gianfranco Alpini, Giammarco Fava, Yoshiyuki Ueno, Jo Lynne Phinizy, Ramona Reichenbach, Marco Marzioni, Domenico Alvaro, Luca Marucci, Heather Francis, Antonio Benedetti, Julie Venter, Silvia Taffetani, Shannon Glaser, Gene LeSage |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Male
medicine.medical_specialty proliferation Cholangiocyte proliferation camp Biology bicarbonate secretion Cholangiocyte erk cytokeratin-19 chemistry.chemical_compound bovine serum albumin Internal medicine ck-19 Cyclic AMP medicine Animals Secretion Enzyme Inhibitors Biliary Tract Extracellular Signal-Regulated MAP Kinases extracellular signal-regulated kinase Cell Proliferation bsa Forskolin Hepatology biliary epithelium MEK inhibitor Colforsin Epithelial Cells MAP Kinase Kinase Kinases Cyclic AMP-Dependent Protein Kinases Hormones Rats Inbred F344 Epithelium Rats secretin receptor Isoenzymes src-Family Kinases medicine.anatomical_structure Endocrinology Liver chemistry Apoptosis cyclic adenosine 3′ 5′-monophosphate Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Journal of Hepatology. 41:528-537 |
| ISSN: | 0168-8278 |
| DOI: | 10.1016/j.jhep.2004.06.009 |
| Popis: | Background/Aims To evaluate if increased cholangiocyte cAMP levels alone are sufficient to enhance cholangiocyte proliferation and secretion. Methods Normal rats were treated in vivo with forskolin for two weeks. Cholangiocyte apoptosis, proliferation and secretion were evaluated. Purified cholangiocytes from normal rats were treated in vitro with forskolin in the absence or presence of Rp-cAMPs (a PKA inhibitor), PP2 (an Src inhibitor) or PD98059 (a MEK inhibitor). Subsequently, we evaluated cholangiocyte proliferation by determination of proliferating cellular nuclear antigen (PCNA) protein expression by immunoblots. We evaluated if the effects of forskolin on cholangiocyte functions are associated with changes in the cAMP/PKA/Src/MEK/ERK1/2 pathway. Results Chronic administration of forskolin to normal rats increased the number of ducts, cAMP levels, and secretin-induced choleresis compared to controls. Forskolin-induced increases in cholangiocyte proliferation and secretion were devoid of cholangiocyte necrosis, inflammation and apoptosis. In vitro, in pure isolated cholangiocytes, forskolin increased cholangiocyte proliferation, which was ablated by Rp-cAMPs, PP2 and PD98059. The effects of forskolin on cholangiocyte proliferation were associated with increased activity of PKA, Src Tyrosine 139 (Tyr 139) and ERK1/2. Conclusions Modulation of the PKA/Src/MEK/ERK1/2 pathway may be important in the regulation of cholangiocyte growth and secretion observed in cholestatic liver diseases. |
| Databáze: | OpenAIRE |
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