Suppressor of cytokine signalling-3 inhibits tumor necrosis factor-alpha induced apoptosis and signalling in beta cells

Bruun, Christine; Heding, Peter E.; Rønn, Sif G.; Frobøse, H; Rhodes, Christopher J.; Mandrup-Poulsen, Thomas; Billestrup, Nils

doi:10.1016/j.mce.2009.07.019

Cited by 36 publications

(36 citation statements)

References 35 publications

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“…Recent data from our laboratory demonstrate that in pancreatic beta cells SOCS3, induced by cytokines, interacts with the insulin receptor, inhibiting the recruitment of IRS proteins and hence downstream signals [14]. Several studies from Billestrup et al reported that SOCS3 constitutively produced in beta cells reduces cytokine [15,16] and GH [9,17] signals in these cells. Indeed, the latter observations clearly demonstrate the important role of SOCS3 in inhibiting deleterious cytokine signalling in beta cells and hence favouring islet survival [15,16].…”

Section: Introductionmentioning

confidence: 89%

“…Several studies from Billestrup et al reported that SOCS3 constitutively produced in beta cells reduces cytokine [15,16] and GH [9,17] signals in these cells. Indeed, the latter observations clearly demonstrate the important role of SOCS3 in inhibiting deleterious cytokine signalling in beta cells and hence favouring islet survival [15,16]. In addition, using a mouse model producing SOCS3 constitutively in beta cells, Billestrup et al revealed the implication of SOCS3 in the regulation of GH signalling in the endocrine pancreas [9].…”

Section: Introductionmentioning

confidence: 99%

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The suppressor of cytokine signalling 2 (SOCS2) is a key repressor of insulin secretion

et al. 2010

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Aims/hypothesis Suppressor of cytokine signalling (SOCS) proteins are powerful inhibitors of pathways involved in survival and function of pancreatic beta cells. Whereas SOCS1 and SOCS3 have been involved in immune and inflammatory processes, respectively, in beta cells, nothing is known about SOCS2 implication in the pancreas. Methods Transgenic (tg) mice were generated that constitutively produced SOCS2 in beta cells (βSOCS2) to define whether this protein is implicated in beta cell functioning and/or survival.Results Constitutive production of SOCS2 in beta cells leads to hyperglycaemia and glucose intolerance. This phenotype is not a consequence of decreased beta cell mass or inhibition of insulin synthesis. However, insulin secretion to various secretagogues is profoundly altered in intact animals and isolated islets. Interestingly, constitutive SOCS2 production dampens the rise in cytosolic free calcium concentration induced by glucose, while glucose metabolism is unchanged. Moreover, tg islets have a depletion in endoplasmic reticulum Ca 2+ stores, suggesting that SOCS2 interferes with calcium fluxes. Finally, inElectronic supplementary material The online version of this article

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Section: Introductionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

The suppressor of cytokine signalling 2 (SOCS2) is a key repressor of insulin secretion

et al. 2010

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“…The wild-type LepR strongly induced the antiapoptotic SOCS3 gene (9), while the STAT3 mutant LepR displayed increased transcription of proapoptotic genes. These results suggest that downregulation of proapoptotic genes via SOCS3 and other transcriptional repressors may be the main mechanism of increased resistance to amebic cytotoxicity regulated via LepR.…”

Section: Fig 3 Mutation Of Intracellular Signaling Tyrosines Revealedmentioning

confidence: 96%

Leptin Protects Host Cells from Entamoeba histolytica Cytotoxicity by a STAT3-Dependent Mechanism

et al. 2012

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ABSTRACTThe adipocytokine leptin links nutritional status to immune function. Leptin signaling protects from amebiasis, but the molecular mechanism is not understood. We developed anin vitromodel of ameba-host cell interaction to test the hypothesis that leptin prevents ameba-induced apoptosis in host epithelial cells. We demonstrated that activation of mammalian leptin signaling increased cellular resistance to amebic cytotoxicity, including caspase-3 activation. Exogenous expression of the leptin receptor conferred resistance in susceptible cells, and leptin stimulation enhanced protection. A series of leptin receptor signaling mutants showed that resistance to amebic cytotoxicity was dependent on activation of STAT3 but not the Src homology-2 domain-containing tyrosine phosphatase (SHP-2) or STAT5. A common polymorphism in the leptin receptor (Q223R) that increases susceptibility to amebiasis in humans and mice was found to increase susceptibility to amebic cytotoxicity in single cells. The Q223R polymorphism also decreased leptin-dependent STAT3 activation by 21% relative to that of the wild-type (WT) receptor (P= 0.035), consistent with a central role of STAT3 signaling in protection. A subset of genes uniquely regulated by STAT3 in response to leptin was identified. Most notable were the TRIB1 and suppressor of cytokine signaling 3 (SOCS3) genes, which have opposing roles in the regulation of apoptosis. Overall apoptotic genes were highly enriched in this gene set (P< 1E−05), supporting the hypothesis that leptin regulation of host apoptotic genes via STAT3 is responsible for protection. This is the first demonstration of a mammalian signaling pathway that restricts amebic pathogenesis and represents an important advance in our mechanistic understanding of how leptin links nutrition and susceptibility to infection.

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“…It is also shown to inhibit cell cycle progression, suppressing the androgen-mediated proliferation of prostate cancer cells (34). In contrast, SOCS3 suppressed the cytokine-induced apoptosis of pancreatic b cells (35). Similarly, SOCS1 has been reported for antiapoptotic effects.…”

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confidence: 98%

Suppressors of Cytokine Signaling Promote Fas-Induced Apoptosis through Downregulation of NF-κB and Mitochondrial Bfl-1 in Leukemic T Cells

Kim

Ahn

et al. 2012

The Journal of Immunology

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Suppressors of cytokine signaling (SOCS) are known as negative regulators of cytokine- and growth factor–induced signal transduction. Recently they have emerged as multifunctional proteins with regulatory roles in inflammation, autoimmunity, and cancer. We have recently reported that SOCS1 has antiapoptotic functions against the TNF-α– and the hydrogen peroxide–induced T cell apoptosis through the induction of thioredoxin, which protects protein tyrosine phosphatases and attenuates Jaks. In this study, we report that SOCS, on the contrary, promote death receptor Fas-mediated T cell apoptosis. The proapoptotic effect of SOCS1 was manifested with increases in Fas-induced caspase-8 activation, truncated Bid production, and mitochondrial dysfunctions. Both caspase-8 inhibitor c-Flip and mitochondrial antiapoptotic factor Bfl-1 were significantly reduced by SOCS1. These proapoptotic responses were not associated with changes in Jak or p38/Jnk activities but were accompanied with downregulation of NF-κB and NF-κB–dependent reporter gene expression. Indeed, p65 degradation via ubiquitination was accelerated in SOCS1 overexpressing cells, whereas it was attenuated in SOCS1 knockdown cells. With high NF-κB levels, the SOCS1-ablated cells displayed resistance against Fas-induced apoptosis, which was abrogated upon siBfl-1 transfection. The results indicate that the suppression of NF-κB–dependent induction of prosurvival factors, such as Bfl-1 and c-Flip, may serve as a mechanism for SOCS action to promote Fas-mediated T cell apoptosis. SOCS3 exhibited a similar proapoptotic function. Because both SOCS1 and SOCS3 are induced upon TCR stimulation, SOCS would play a role in activation-induced cell death by sensitizing activated T cells toward Fas-mediated apoptosis to maintain T cell homeostasis.

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Suppressor of cytokine signalling-3 inhibits tumor necrosis factor-alpha induced apoptosis and signalling in beta cells

Cited by 36 publications

References 35 publications

The suppressor of cytokine signalling 2 (SOCS2) is a key repressor of insulin secretion

The suppressor of cytokine signalling 2 (SOCS2) is a key repressor of insulin secretion

Leptin Protects Host Cells from Entamoeba histolytica Cytotoxicity by a STAT3-Dependent Mechanism

Suppressors of Cytokine Signaling Promote Fas-Induced Apoptosis through Downregulation of NF-κB and Mitochondrial Bfl-1 in Leukemic T Cells

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