Effect of protein kinase C activation and inhibition on rat hepatic stellate cell activation.
Protein kinase C (PKC) may play a role in the intracellular signaling pathways responsible for transforming hepatic stellate cells into myofibroblasts. This study examined the effects of inhibitors and activators of PKC on hepatic stellate cell activation. Stellate cells isolated from normal rats were incubated with either 10(-5) M chelerythrine, 10(-7) M bisindolylmaleimide I hydrochloride (BIM), or 10(-6) M staurosporine (PKC inhibitors), or 10(-7) M phorbol myristate acetate (PMA) or 10(-6) M thymeleatoxin (PKC activators). Chelerythrine suppressed alpha-smooth muscle actin expression and proliferation by 49% and 33%, respectively. BIM inhibited alpha-smooth muscle actin expression by 60%, but had no significant effect on proliferation. Staurosporine decreased proliferation by 86% and completely prevented alpha-smooth muscle actin expression. PKC activators had divergent effects on proliferation and alpha-smooth muscle actin expression. PMA and thymeleatoxin caused a 2.8- to 3.2-fold increase in proliferation, while suppressing alpha-smooth muscle actin expression by 50-70%. The demonstration that hepatic stellate cell activation can be suppressed by PKC inhibitors suggests a role for PKC in the regulation of hepatic stellate cell activation.
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, Missouri 63110-0250, USA.
Grant A
GA
Ramm
Lin
L
Li
Robert S
RS
Britton
Rosemary
R
O'Neill
Bruce R
BR
Bacon
D000199:Actins / Q000378:metabolism; D000470:Alkaloids; D000818:Animals; D053119:Benzophenanthridines; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008099:Liver / Q000166:cytology*; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D010617:Phenanthridines / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D019311:Staurosporine / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000199:Actins; D000470:Alkaloids; D053119:Benzophenanthridines; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D010617:Phenanthridines; D010703:Phorbol Esters; C080287:thymeleatoxin; C016299:chelerythrine; D011493:Protein Kinase C; D019311:Staurosporine; C070515:bisindolylmaleimide I; D013755:Tetradecanoylphorbol Acetate