Cytokines induce both necrosis and apoptosis via a common Bcl-2-inhibitable pathway in rat insulin-producing cells

Endocrinology. 2000 Jun;141(6):2003-10. doi: 10.1210/endo.141.6.7523.


The presence of activated macrophages within pancreatic islets in insulin-dependent diabetes mellitus suggests an involvement of beta-cell death by necrosis. The aim of this study was to investigate the frequencies and mechanisms of cytokine-induced beta-cell apoptosis and necrosis and the possible protection mediated by the antiapoptotic gene bcl-2. A combination of interleukin-1beta, interferon-gamma, and tumor necrosis factor-alpha increased both necrosis (17% of cells) and apoptosis (5% of cells) in isolated whole rat islets, as determined by vital staining and fluorescence microscopy. Hyperexpression of Bcl-2, achieved by stable transfection using a multicopy viral vector containing a bcl-2 complementary DNA in rat insulin-producing RINm5F cells, counteracted both apoptosis and necrosis. Cytokine-induced cleavage of the caspase-3 substrate poly(ADP-ribose) polymerase (which, in other cell types, may occur downstream or independently of a Bcl-2-preventable mitochondrial permeability transition) was observed in control- but neither in bcl-2-transfected cells nor in the presence of the iNOS inhibitor N(G)-methyl-L-arginine. Tumor necrosis factor-alpha alone did not clearly induce cell death or poly(ADP-ribose) polymerase-cleavage. These findings suggest that cytokines induce both necrosis and apoptosis in insulin-producing cells via a common Bcl-2-preventable nitric oxide-dependent pathway, which may involve mitochondrial permeability transition. The necrosis:apoptosis ratio might be increased by a relative lack of caspase activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Caspase 3
  • Caspases / metabolism
  • Cells, Cultured
  • Cytokines / pharmacology*
  • Gene Expression
  • Insulin / biosynthesis*
  • Interferon-gamma / pharmacology
  • Interleukin-2 / pharmacology
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology*
  • Male
  • Necrosis
  • Nitric Oxide / metabolism
  • Poly(ADP-ribose) Polymerases / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / pharmacology
  • Proto-Oncogene Proteins c-bcl-2 / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Transfection
  • Tumor Necrosis Factor-alpha / pharmacology
  • omega-N-Methylarginine / pharmacology


  • Cytokines
  • Insulin
  • Interleukin-2
  • Proto-Oncogene Proteins c-bcl-2
  • Tumor Necrosis Factor-alpha
  • omega-N-Methylarginine
  • Nitric Oxide
  • Interferon-gamma
  • Poly(ADP-ribose) Polymerases
  • Casp3 protein, rat
  • Caspase 3
  • Caspases