IL-1β-induced chemokine and Fas expression are inhibited by suppressor of cytokine signalling-3 in insulin-producing cells

Jacobsen, Marianne; Rønn, Sif G.; Bruun, Christine; Larsen, Claus M.; Eizirik, Décio L.; Mandrup-Poulsen, Thomas; Billestrup, Nils

doi:10.1007/s00125-008-1199-1

Cited by 22 publications

(15 citation statements)

References 39 publications

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“…Our observation was supported by numerous studies. For example, Jacobsen et al reported that IL-1β induced insulin-producing cell apoptosis through the Fas-mediated apoptotic signaling pathway (25). We also observed that PVAE administration significantly attenuated IL-1β-induced increases in JNK phosphorylation in INS-1 cells.…”

Section: Discussionsupporting

confidence: 72%

Prunella vulgaris aqueous extract attenuates IL-1β-induced apoptosis and NF-κB activation in INS-1 cells

Gao

et al. 2012

Experimental and Therapeutic Medicine

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Abstract. We previously reported that Prunella vulgaris aqueous extract (PVAE) promotes hepatic glycogen synthesis and decreases postprandial hyperglycemia in ICR mice. Inflammatory cytokines play a critical role in the pathogenesis of diabetes. This study was designed to examine whether PVAE has a protective effect on IL-1β-induced apoptosis in INS-1 cells. INS-1 pancreatic β cells were plated at 2x10 6 /ml and treated with PVAE (100 µg/ml) 30 min before the cells were challenged with IL-1β (10 ng/ml). Untreated INS-1 cells served as control. INS-1 cell cytotoxicity was examined by MTT and lactate dehydrogenase (LDH) activity assays. Caspase-3 activity and activation of the apoptotic signaling pathway were analyzed by western blotting. NF-κB binding activity was examined by EMSA. The levels of inflammatory cytokines in the supernatant were measured by ELISA. IL-1β treatment significantly induced INS-1 cell death by 49.2%, increased LDH activity by 1.5-fold and caspase-3 activity by 7.6-fold, respectively, compared with control cells. However, PVAE administration significantly prevented IL-1β-increased INS-1 cell death and LDH activity and attenuated IL-1β-increased caspase-3 activity. Western blot data showed that PVAE also significantly attenuated IL-1β-increased Fas, FasL and phospho-JNK levels in the INS-1 cells. In addition, PVAE treatment significantly attenuated IL-1β-increased NF-κB binding activity and prevented IL-1β-increased TNF-α and IL-6 expression in INS-1 cells. Our data suggest that PVAE has a protective effect on IL-1β-induced INS-1 cell apoptosis. PVAE also attenuates IL-1β-increased NF-κB binding activity and inflammatory cytokine expression in INS-1 cells. PVAE may have a benefit for type I diabetic patients.

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Section: Discussionsupporting

confidence: 72%

Prunella vulgaris aqueous extract attenuates IL-1β-induced apoptosis and NF-κB activation in INS-1 cells

Gao

et al. 2012

Experimental and Therapeutic Medicine

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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: 91%

“…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%

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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“…These findings suggest the NF- k B signalling is blocked or severely impaired, as confirmed by the absence of expression of its downstream genes, i.e. iNOS (inducible nitric oxide synthase) [30], MnSOD (Manganese superoxide dismutase, a free radical scavenger) and FAS (CD95) [41], [42].…”

Section: Discussionmentioning

confidence: 82%

In Vitro Phenotypic, Genomic and Proteomic Characterization of a Cytokine-Resistant Murine β-TC3 Cell Line

et al. 2012

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Type 1 diabetes mellitus (T1DM) is caused by the selective destruction of insulin-producing β-cells. This process is mediated by cells of the immune system through release of nitric oxide, free radicals and pro-inflammatory cytokines, which induce a complex network of intracellular signalling cascades, eventually affecting the expression of genes involved in β-cell survival.The aim of our study was to investigate possible mechanisms of resistance to cytokine-induced β-cell death. To this purpose, we created a cytokine-resistant β-cell line (β-TC3R) by chronically treating the β-TC3 murine insulinoma cell line with IL-1β + IFN-γ. β-TC3R cells exhibited higher proliferation rate and resistance to cytokine-mediated cell death in comparison to the parental line. Interestingly, they maintained expression of β-cell specific markers, such as PDX1, NKX6.1, GLUT2 and insulin. The analysis of the secretory function showed that β-TC3R cells have impaired glucose-induced c-peptide release, which however was only moderately reduced after incubation with KCl and tolbutamide. Gene expression analysis showed that β-TC3R cells were characterized by downregulation of IL-1β and IFN-γ receptors and upregulation of SOCS3, the classical negative regulator of cytokines signaling. Comparative proteomic analysis showed specific upregulation of 35 proteins, mainly involved in cell death, stress response and folding. Among them, SUMO4, a negative feedback regulator in NF-kB and JAK/STAT signaling pathways, resulted hyper-expressed. Silencing of SUMO4 was able to restore sensitivity to cytokine-induced cell death in β-TC3R cells, suggesting it may play a key role in acquired cytokine resistance by blocking JAK/STAT and NF-kB lethal signaling.In conclusion, our study represents the first extensive proteomic characterization of a murine cytokine-resistant β-cell line, which might represent a useful tool for studying the mechanisms involved in resistance to cytokine-mediated β-cell death. This knowledge may be of potential benefit for patients with T1DM. In particular, SUMO4 could be used as a therapeutical target.

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IL-1β-induced chemokine and Fas expression are inhibited by suppressor of cytokine signalling-3 in insulin-producing cells

Cited by 22 publications

References 39 publications

Prunella vulgaris aqueous extract attenuates IL-1β-induced apoptosis and NF-κB activation in INS-1 cells

Prunella vulgaris aqueous extract attenuates IL-1β-induced apoptosis and NF-κB activation in INS-1 cells

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

In Vitro Phenotypic, Genomic and Proteomic Characterization of a Cytokine-Resistant Murine β-TC3 Cell Line

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