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

J Saldeen - Endocrinology, 2000 - academic.oup.com
J Saldeen
Endocrinology, 2000academic.oup.com
The presence of activated macrophages within pancreatic islets in insulin-dependent
diabetes mellitus suggests an involvement of β-cell death by necrosis. The aim of this study
was to investigate the frequencies and mechanisms of cytokine-induced β-cell apoptosis
and necrosis and the possible protection mediated by the antiapoptotic gene bcl-2. A
combination of interleukin-1β, interferon-γ, and tumor necrosis factor-α increased both
necrosis (17% of cells) and apoptosis (5% of cells) in isolated whole rat islets, as determined …
Abstract
The presence of activated macrophages within pancreatic islets in insulin-dependent diabetes mellitus suggests an involvement of β-cell death by necrosis. The aim of this study was to investigate the frequencies and mechanisms of cytokine-induced β-cell apoptosis and necrosis and the possible protection mediated by the antiapoptotic gene bcl-2. A combination of interleukin-1β, interferon-γ, and tumor necrosis factor-α 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 NG-methyl-l-arginine. Tumor necrosis factor-α 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.
Oxford University Press