Double-Stranded RNA—Dependent Protein Kinase Is Not Required for Double-Stranded RNA—Induced Nitric Oxide Synthase Expression or Nuclear Factor-κB Activation by Islets

Blair, Libby A.; Heitmeier, Monique R.; Scarim, Anna L.; Maggi, Leonard B.; Corbett, John A.

doi:10.2337/diabetes.50.2.283

Cited by 23 publications

(14 citation statements)

References 51 publications

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“…However, neither IFN-␣ nor IFN-␥ altered the expression level of this protein (C57BL6, n ϭ 4; data not shown). Finally, we observed that islet cells expressed PKR, extending previous results demonstrating PKR mRNA expression by islets (31). Treatment with IFN-␣ led to a 2.4-fold increase in PKR expression (Fig.…”

Section: Ifns Increase the Expression Of 2-5as And Pkrsupporting

confidence: 78%

RNase L and Double-Stranded RNA-Dependent Protein Kinase Exert Complementary Roles in Islet Cell Defense during Coxsackievirus Infection

Flodström‐Tullberg

Hultcrantz

Stotland

et al. 2005

The Journal of Immunology

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Coxsackievirus (CV) is an important human pathogen that has been linked to the development of autoimmunity. An intact pancreatic β cell IFN response is critical for islet cell survival and protection from type 1 diabetes following CV infection. In this study, we show that IFNs trigger an antiviral state in β cells by inducing the expression of proteins involved in intracellular antiviral defense. Specifically, we demonstrate that 2′,5′-oligoadenylate synthetases (2-5AS), RNase L, and dsRNA-dependent protein kinase (PKR) are expressed by pancreatic islet cells and that IFNs (IFN-α and IFN-γ) increase the expression of 2-5AS and PKR, but not RNase L. Moreover, our in vitro studies uncovered that these pathways play important roles in providing unique and complementary antiviral activities that critically regulate the outcome of CV infection. The 2-5AS/RNase L pathway was critical for IFN-α-mediated islet cell resistance from CV serotype B4 (CVB4) infection and replication, whereas an intact PKR pathway was required for efficient IFN-γ-mediated repression of CVB4 infection and replication. Finally, we show that the 2-5AS/RNase L and the PKR pathways play important roles for host survival during a challenge with CVB4. In conclusion, this study has dissected the pathways used by distinct antiviral signals and linked their expression to defense against CVB4.

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Section: Ifns Increase the Expression Of 2-5as And Pkrsupporting

confidence: 78%

RNase L and Double-Stranded RNA-Dependent Protein Kinase Exert Complementary Roles in Islet Cell Defense during Coxsackievirus Infection

Flodström‐Tullberg

Hultcrantz

Stotland

et al. 2005

The Journal of Immunology

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“…64,65 The effect of IFNs is intensified by dsRNA that can inhibit b-cell function and induce islet damage by its own. 54,66 Interestingly, insulin-dependent diabetes mellitus was reported to occur also after treatment of viral hepatitis patients with exogenous IFNs. 67,68 The identification of pathways and molecules involved in dsRNA-induced apoptosis and necrosis will hopefully lead to a better understanding of the role of this mode of cell death in immune responses and pathologies.…”

Section: Discussionmentioning

confidence: 99%

Tipping the balance between necrosis and apoptosis in human and murine cells treated with interferon and dsRNA

et al. 2002

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Interferons enhance the cellular antiviral response by inducing expression of protective proteins. Many of these proteins are activated by dsRNA, a typical by-product of viral infection. Here we show that type-I and type-II interferons can sensitize cells to dsRNA-induced cytotoxicity. In caspase-8-or FADD-deficient Jurkat cells dsRNA induces necrosis, instead of apoptosis. In L929sA cells dsRNA-induced necrosis involves high reactive oxygen species production. The antioxidant butylated hydroxyanisole protects cells from necrosis, but shifts the response to apoptosis. Treatment with the caspase inhibitor benzyloxycarbonyl-Val-Ala-DLAsp(OMe)-fluoromethylketone or overexpression of Bcl-2 prevent this shift and promote necrosis. Our results suggest that a single stimulus can initiate different deathsignaling pathways, leading to either necrotic or apoptotic cell death. Inhibition of key events in these signaling pathways, such as caspase activation, cytochrome c release or mitochondrial reactive oxygen species production, tips the balance between necrosis and apoptosis, leading to dominance of one of these death programs.

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“…Studies have shown that poly(I:C) could induce apoptosis of pancreatic islets (11,13,31). To examine whether this is also the case in our experimental system, we cultured the freshly handpicked pancreatic islets from B6/RIP-B7.1 mice in the presence or absence of 100 g/ml poly(I:C).…”

Section: Poly(i:c) Induced Augmented Apoptosis Of Pancreatic Isletsmentioning

confidence: 99%

The Effect of Innate Immunity on Autoimmune Diabetes and the Expression of Toll-Like Receptors on Pancreatic Islets

Peng

et al. 2004

The Journal of Immunology

128

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Viral infections have previously been implicated as a trigger of autoimmune diabetes. In this study, we compared a viral mimic with other microbial components derived from bacteria in triggering diabetes development in C57BL/6-rat insulin promoter-B7.1 mice that do not normally develop diabetes. It is striking that only the viral mimic induced the development of diabetes in our model system. Further mechanistic studies suggest that diabetes is induced, in part, by the combination of direct recognition of this virus-like stimulus by pancreatic islets through the expression of the innate immune receptor, Toll-like receptor 3. In addition, the functions of APCs are up-regulated, and this could stimulate islet Ag-reactive T cells that will attack β cells leading to autoimmune diabetes.

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Double-Stranded RNA—Dependent Protein Kinase Is Not Required for Double-Stranded RNA—Induced Nitric Oxide Synthase Expression or Nuclear Factor-κB Activation by Islets

Cited by 23 publications

References 51 publications

RNase L and Double-Stranded RNA-Dependent Protein Kinase Exert Complementary Roles in Islet Cell Defense during Coxsackievirus Infection

RNase L and Double-Stranded RNA-Dependent Protein Kinase Exert Complementary Roles in Islet Cell Defense during Coxsackievirus Infection

Tipping the balance between necrosis and apoptosis in human and murine cells treated with interferon and dsRNA

The Effect of Innate Immunity on Autoimmune Diabetes and the Expression of Toll-Like Receptors on Pancreatic Islets

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