Baculovirus p35 increases pancreatic beta-cell resistance to apoptosis.
beta-cells die by apoptosis in type 1 diabetes as a result of autoimmune attack mediated by cytokines, and in type 2 diabetes by various perpetrators including human islet amyloid polypeptide (hIAPP). The cascade of apoptotic events induced by cytokines and hIAPP is mediated through caspases and reactive oxygen species. The baculovirus p35 protein is a potent anti-apoptotic agent shown to be effective in a variety of species and able to inhibit a number of apoptotic pathways. Here, we aimed at determining the protective potential of p35 in beta-cells exposed to cytokines and hIAPP, as well as the effects of p35 on beta-cell function. The p35 gene was introduced into betaTC-tet cells, a differentiated murine beta-cell line capable of undergoing inducible growth-arrest. Both proliferating and growth-arrested cells expressing p35 manifested increased resistance to cytokines and hIAPP, compared with control cells, as judged by cell viability, DNA fragmentation, and caspase-3 activity assays. p35 was significantly more protective in growth-arrested, compared with proliferating, cells. No significant differences were observed in proliferation and insulin content between cells expressing p35 and control cells. In contrast, p35 manifested a perturbing effect on glucose-induced insulin secretion. These findings suggest that p35 could be incorporated as part of a multi-pronged approach of immunoprotective strategies to provide protection from recurring autoimmunity for transplanted beta-cells, as well as in preventive gene therapy in type 1 diabetes. p35 may also be protective from beta-cell damage caused by hIAPP in type 2 diabetes.
Hollander
Kenneth
K
Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel.
Bar-Chen
Michal
M
Efrat
Shimon
S
D000682:Amyloid / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D016207:Cytokines / Q000494:pharmacology; D007113:Immunity, Innate / Q000187:drug effects / Q000502:physiology*; D058228:Islet Amyloid Polypeptide; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection / Q000379:methods; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism*
D000682:Amyloid; D016207:Cytokines; D058228:Islet Amyloid Polypeptide; D011994:Recombinant Proteins; D014764:Viral Proteins; C492234:p35 protein, Baculovirus