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- Title
Stat5b and Nkx6.1 Confer Discrete and Complementary Protective Effects Against Cytokine-Mediated Cell Death and Impairment of Glucose-Stimulated Insulin Secretion.
- Authors
Collier, J. J.; Schisler, Jonathan C.; Lu, Danhong; Fueger, Patrick T.; Hohmeier, Hans E.; Newgard, Christopher B.
- Abstract
The proinflammatory cytokines interleukin-1β (IL-1β) and γ-interferon (γ-IFN) contribute significantly to death and dysfunction of pancreatic β-cells leading to Type 1 diabetes. Exposure of 832/13 rat insulinoma cells to 10ng/mL IL-1β and 100U/mL γ-IFN for 24h caused a 50% decrease in cell viability as measured by MTT assay and a 55% decrease in cell proliferation as measured by 3H thymidine incorporation. Six hours of incubation with these same cytokines reduced glucose-stimulated insulin secretion (GSIS) by 60%. The transcription factors Nkx6.1 and Stat5b have recently been ascribed roles in control of β-cell replication and function. Overexpression of Nkx6.1, but not constitutively-active Stat5b (CAStat5b), improved GSIS by 37% (p<0.05) in the presence of cytokines. Conversely, expression of CAStat5b, but not Nkx6.1, enhanced viability (82% viable vs. 47% viable for control or Nkx6. l-treated cells, (p<0.05) during 24 h of cytokine exposure, and prevented the cytokine-mediated decrease in proliferation in both islets and 832/13 cells. To determine if changes in proliferative capacity are required for the survival phenotype induced by CAStat5b overexpression, we used siRNA duplexes to suppress expression of the cyclin D2 gene, a known regulator of cellular proliferation and a direct Stat5b target gene. An 80% suppression of cyclin D2 mRNA levels lead to a 48% decrease in 3H-thymidine incorporation, but CAStat5b retained complete ability to protect 832/13 cells against cytokine-mediated cytotoxicity as assessed by the MTT and adenylate kinase viability assays. We conclude that Stat5b and Nkx6.1 confer discrete and complementary protective effects against cytokine-mediated damage of β-cells, with Nkx6.1 providing protection against functional impairment, and Stat5b protecting against loss of cell mass and function. ADA-Funded Research
- Subjects
TRANSCRIPTION factors; CYTOKINES; CELL death; GLUCOSE; INTERLEUKIN-1; PANCREATIC beta cells; INSULIN; DIABETES
- Publication
Diabetes, 2007, Vol 56, pA444
- ISSN
0012-1797
- Publication type
Article