Suppressor of cytokine signaling-1 inhibits caspase activation  and protects from cytokine-induced beta cell death.
Pancreatic beta cell damage caused by proinflammatory cytokines interleukin-1beta (IL-1beta), interferon-gamma (IFNgamma) and tumor necrosis factor-alpha (TNFalpha) is a key event in the pathogenesis of type 1 diabetes. The suppressor of cytokine signaling-1 (SOCS-1) blocks IFNgamma-induced signaling and prevents diabetes in the non-obese diabetic mouse. Here, we investigated if SOCS-1 overexpression in primary beta cells provides protection from cytokine-induced islet cell dysfunction and death. We demonstrate that SOCS-1 does not prevent increase in NO production and decrease in glucose-stimulated insulin secretion in the presence of IL-1beta, IFNgamma, TNFalpha. However, it decreases the activation of caspase-3, -8 and -9, and thereby, promotes a robust protection from cytokine-induced beta cell death. Our data suggest that SOCS-1 overexpression may not be sufficient in preventing all the biological activities of IFNgamma in beta cells. In summary, we show that interference with IFNgamma signal transduction pathways by SOCS-1 inhibits cytokine-stimulated pancreatic beta cell death.
Zaitseva
Irina I
II
The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, L1, 171 76 Stockholm, Sweden.
Hultcrantz
Monica
M
Sharoyko
Vladimir
V
Flodström-Tullberg
Malin
M
Zaitsev
Sergei V
SV
Berggren
Per-Olof
PO
D000818:Animals; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000502:physiology; D007371:Interferon-gamma / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000502:physiology*
D016207:Cytokines; D007328:Insulin; D050791:STAT Transcription Factors; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D009569:Nitric Oxide; D007371:Interferon-gamma; D053612:Janus Kinases; D020169:Caspases