Expression of the Transcription Factor STAT-1α in Insulinoma Cells Protects against Cytotoxic Effects of Multiple Cytokines

Document Type

Article

Publication Date

1-2001

Abstract

Destruction of pancreatic islet β-cells in type 1 diabetes appears to result from direct contact with infiltrating T-cells and macrophages and exposure to inflammatory cytokines such as interferon (IFN)-γ, interleukin (IL)-1β, and tumor necrosis factor TNF-α that such cells produce. We recently reported on a method for selection of insulinoma cells that are resistant to the cytotoxic effects of inflammatory cytokines (INS-1res), involving their growth in progressively increasing concentrations of IL-1β plus IFN-γ, and selection of surviving cells. In the current study, we have investigated the molecular mechanism of cytokine resistance in INS-1rescells. By focusing on the known components of the IFN-γ receptor signaling pathway, we have discovered that expression levels of signal transducer and activator of transcription (STAT)-1α are closely correlated with the cytokine-resistant and -sensitive phenotypes. That STAT-1α is directly involved in development of cytokine resistance is demonstrated by an increase of viability from 10 ± 2% in control cells to 50 ± 6% in cells with adenovirus-mediated overexpression of STAT-1α (p < 0.001) after culture of both cell groups in the presence of 100 units/ml IFN-γ plus 10 ng/ml IL-1β for 48 h. The resistance to IL-1β plus IFN-γ in STAT-1α-expressing cells is due in part to interference with IL-1β-mediated stimulation of inducible nitric-oxide synthase expression and nitric oxide production. Furthermore, overexpression of STAT-1α does not impair robust glucose-stimulated insulin secretion in the INS-1-derived cell line 832/13. We conclude that expression of STAT-1α may be a means of protecting insulin-producing cell lines from cytokine damage, which, in conjunction with appropriate cell-impermeant macroencapsulation devices, may allow such cells to be used for insulin replacement in type 1 diabetes.

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