SOCS-1 Protein Prevents Janus Kinase/STAT-dependent Inhibition of beta Cell Insulin Gene Transcription and Secretion in Response to Interferon-gamma (original) (raw)
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Journal of Biological Chemistry, 2001
Destruction of pancreatic islet -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)-␥, interleukin (IL)-1, and tumor necrosis factor TNF-␣ 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-1 res), involving their growth in progressively increasing concentrations of IL-1 plus IFN-␥, and selection of surviving cells. In the current study, we have investigated the molecular mechanism of cytokine resistance in INS-1 res cells. By focusing on the known components of the IFN-␥ receptor signaling pathway, we have discovered that expression levels of signal transducer and activator of transcription (STAT)-1␣ are closely correlated with the cytokine-resistant and-sensitive phenotypes. That STAT-1␣ 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-1␣ (p < 0.001) after culture of both cell groups in the presence of 100 units/ml IFN-␥ plus 10 ng/ml IL-1 for 48 h. The resistance to IL-1 plus IFN-␥ in STAT-1␣-expressing cells is due in part to interference with IL-1-mediated stimulation of inducible nitric-oxide synthase expression and nitric oxide production. Furthermore, overexpression of STAT-1␣ does not impair robust glucosestimulated insulin secretion in the INS-1-derived cell line 832/13. We conclude that expression of STAT-1␣ 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.
Journal of Biological Chemistry, 1999
In this study, the ability of interferon-␥ (IFN-␥) to prime rat and nonobese diabetic (NOD) mouse islets for interleukin-1 (IL-1)-stimulated expression of inducible nitric-oxide synthase (iNOS) has been examined. IL-1induced iNOS expression by rat islets is concentrationdependent with maximal expression occurring in response to 1.0 unit/ml. Individually, neither 0.1 unit/ml IL-1 nor 150 units/ml IFN-␥ stimulates iNOS expression or nitrite production by rat islets. However, a 30 -60-min pulse of rat islets with IFN-␥, followed by washing to remove the cytokine and continued culture with 0.1 unit/ml IL-1 for 40 h, results in iNOS expression and nitrite production to levels similar in magnitude to the individual effects of 1.0 unit/ml IL-1
Hormone Molecular Biology and Clinical Investigation, 2016
Diabetes type 1 is characterized by the failure of beta cells to produce insulin. Suppressor of cytokine signaling (SOCS) proteins are important regulators of the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway. Previous studies have shown that GH can prevent the development of type I diabetes in mice and that SOCS2 deficiency mimics a state of increased GH sensitivity.The elevated sensitivity of SOCS2We show that 6-month-old SOCS2Knockdown of SOCS2 makes mice less sensitive to MLDSTZ. These results are consistent with the proposal that elimination of SOCS2 in pancreatic islets creates a state of β-cell hypersensitivity to GH/PRL that mimics events in pregnancy, and which is protective against MLDSTZ-induced type I diabetes in mice. SOCS2-dependent control of β-cell survival may be of relevance to islet regeneration and survival in transplantation.
IB1 Reduces Cytokine-induced Apoptosis of Insulin-secreting Cells
Journal of Biological Chemistry, 2000
IB1/JIP-1 is a scaffold protein that interacts with upstream components of the c-Jun N-terminal kinase (JNK) signaling pathway. IB1 is expressed at high levels in pancreatic  cells and may therefore exert a tight control on signaling events mediated by JNK in these cells. Activation of JNK by interleukin 1 (IL-1) or by the upstream JNK constitutive activator ⌬MEKK1 promoted apoptosis in two pancreatic  cell lines and decreased IB1 content by 50 -60%. To study the functional consequences of the reduced IB1 content in  cell lines, we used an insulin-secreting cell line expressing an inducible IB1 antisense RNA that lead to a 38% IB1 decrease. Reducing IB1 levels in these cells increased phosphorylation of c-Jun and increased the apoptotic rate in presence of IL-1. Nitric oxide production was not stimulated by expression of the IB1 antisense RNA. Complementary experiments indicated that overexpression of IB1 in insulin-producing cells prevented JNKmediated activation of the transcription factors c-Jun, ATF2, and Elk1 and decreased IL-1-and ⌬MEKK1-induced apoptosis. These data indicate that IB1 plays an anti-apoptotic function in insulin-producing cells probably by controlling the activity of the JNK signaling pathway.
Target Cell Expression of Suppressor of Cytokine Signaling1 Prevents Diabetes in the NOD Mouse
Diabetes, 2003
Although lymphocyte infiltration and islet destruction are hallmarks of diabetes, the mechanisms of -cell destruction are not fully understood. One issue that remains unresolved is whether cytokines play a direct role in -cell death. We investigated whether -cell cytokine signaling contributes to autoimmune type 1 diabetes. We demonstrated that NOD mice harboring