Cyclosporine A blockade of the induction of ornithine decarboxylase activity as a cause of failure of islet cell proliferation and differentiation.
Maintenance of islet cell mass may be one factor that contributes to long-term islet allograft viability. It is important, therefore, to determine whether transplant-related events, such as immunosuppression, interfere with the regenerative capacity of the hormone-producing cellular elements of the islet. To investigate this possibility, we utilized a well-characterized model of islet cell growth in which partial obstruction of the hamster pancreatic duct leads to the induction of duct epithelial cell proliferation in association with endocrine cell differentiation and new islet formation. These changes appear to be mediated by a specific trophic activity (TA) that can be extracted from the pancreas following obstruction. Since the trophic effects of many growth factors are mediated through the polyamine pathway, we postulated that the trophic effect of TA is associated with the induction of ornithine decarboxylase (ODC) activity, the rate-limiting step in polyamine biosynthesis. The effect of TA on pancreatic ODC activity was studied alone, and after pretreatment with cyclosporine A (CsA), an immunosuppressive agent that is known to inhibit ODC activity. Eight h following the administration of TA, pancreatic ODC activity increased approximately 6-fold. Pretreatment with CsA for 7 d at a daily dose of 20 mg/kg prevented the induction of pancreatic ODC activity. We conclude that, in this model, CsA can block islet cell proliferation, and that this may be mediated by inhibition of TA-stimulated ODC activity.
Hornby
L
L
Department of Surgery, McGill University, Montreal, Quebec.
Metrakos
P
P
Rosenberg
L
L
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D006224:Cricetinae; D016572:Cyclosporine / Q000494:pharmacology*; D005260:Female; D007515:Islets of Langerhans / Q000166:cytology*; D008647:Mesocricetus; D009955:Ornithine Decarboxylase / Q000096:biosynthesis; D065108:Ornithine Decarboxylase Inhibitors; D010179:Pancreas / Q000201:enzymology*
D065108:Ornithine Decarboxylase Inhibitors; D016572:Cyclosporine; D009955:Ornithine Decarboxylase