Interferon-γ Increases the Sensitivity of Islets of Langerhans for Inducible Nitric-oxide Synthase Expression Induced by Interleukin 1

Heitmeier, Monique R.; Scarim, Anna L.; Corbett, John A.

doi:10.1074/jbc.272.21.13697

Cited by 153 publications

(148 citation statements)

References 37 publications

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“…Inhibition of HDACs affects the NFκB-dependent production of iNOS and formation of NO IL-1β is known to induce expression of the gene encoding iNOS, an effect that is potentiated by IFNγ [18,34]. The subsequent formation of NO drives cell death by both necrosis and apoptosis, at least in rodent beta cells [35].…”

Section: Resultsmentioning

confidence: 99%

Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells

et al. 2007

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Aims/hypothesis The immune-mediated elimination of pancreatic beta cells in type 1 diabetes involves release of cytotoxic cytokines such as IL-1β and IFNγ, which induce beta cell death in vitro by mechanisms that are both dependent and independent of nitric oxide (NO). Nuclear factor kappa B (NFκB) is a critical signalling molecule in inflammation and is required for expression of the gene encoding inducible NO synthase (iNOS) and of proapoptotic genes. NFκB has recently been shown to associate with chromatin-modifying enzymes histone acetyltransferases and histone deacetylases (HDAC), and positive effects of HDAC inhibition have been obtained in several inflammatory diseases. Thus, the aim of this study was to investigate whether HDAC inhibition protects beta cells against cytokine-induced toxicity. Materials and methods The beta cell line, INS-1, or intact rat islets were precultured with HDAC inhibitors suberoylanilide hydroxamic acid or trichostatin A in the absence or presence of IL-1β and IFNγ. Effects on insulin secretion and NO formation were measured by ELISA and Griess reagent, respectively. iNOS levels and NFκB activity were measured by immunoblotting and by immunoblotting combined with electrophoretic mobility shift assay, respectively. Viability was analysed by 3-(4,5-dimethyldiazol-2-yl)-2,5-diphenyl-tetrazolium bromide and apoptosis by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) assay and histone-DNA complex ELISA. Results HDAC inhibition reduced cytokine-mediated decrease in insulin secretion and increase in iNOS levels, NO formation and apoptosis. IL-1β induced a bi-phasic phosphorylation of inhibitor protein kappa Bα (IκBα) with the 2nd peak being sensitive to HDAC inhibition. No effect was seen on IκBα degradation and NFκB DNA binding. Conclusions/interpretation HDAC inhibition prevents cytokine-induced beta cell apoptosis and impaired beta cell function associated with a downregulation of NFκB transactivating activity.

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Section: Resultsmentioning

confidence: 99%

Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells

et al. 2007

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“…It has been previously shown that, whereas IL-1 is a sufficient stimulus for the induction of iNOS mRNA expression and NO production in RIN cells, a combination of IL-1 and IFN-is required for the induction of NO formation by human islets (Cetkovic-Cvrlje and Eizirik, 1994;Eizirik et al, 1996;Heitmeier et al, 1997;Lortz et al, 2000). The increased toxicity of the cytokine combination compared with that of IL-1 alone (Figure 1) is attributable to a significantly higher rate of iNOS mRNA and protein expression (Figure 3) and subsequent NO production ( Figure Figure 5.…”

Section: Discussionmentioning

confidence: 99%

“…In their activated state, T-lymphocytes and macrophages, which are primary cellular components of islet insulitis, secrete high levels of IL-1 and IFN-, respectively. IL-1 alone, or in combination with TNFor IFN-, induces an excess production of nitric oxide (NO) by the iNOS in the pancreatic islets (Cetkovic-Cvrlje and Eizirik, 1994;Corbett and McDaniel, 1995;Heitmeier et al, 1997;Kwon et al, 2003a). Nitric oxide is a short-lived and highly reactive radical, which inhibits the Krebs-cycle enzyme aconitase and electron transport chain complexes I and II, resulting in reduced glucose oxidation rates, ATP generation, and insulin production (Welsh et al, 1991;Corbett et al, 1992;Cunningham and Green, 1994).…”

Section: Introductionmentioning

confidence: 99%

Coptidis rhizoma extract protects against cytokine-induced death of pancreatic β-cells through suppression of NF-κ B activation

Kim

Kwon²,

Han³

et al. 2007

Exp Mol Med

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We demonstrated previously that Coptidis rhizoma extract (CRE) prevented S-nitroso-N-acetylpenicillamine-induced apoptotic cell death via the inhibition of mitochondrial membrane potential disruption and cytochrome c release in RINm5F (RIN) rat insulinoma cells. In this study, the preventive effects of CRE against cytokine-induced β-cell death was assessed. Cytokines generated by immune cells infiltrating pancreatic islets are crucial mediators of β-cell destruction in insulin-dependent diabetes mellitus. The treatment of RIN cells with IL-1β and IFN-γ resulted in a reduction of cell viability. CRE completely protected IL-1β and IFN-γ-mediated cell death in a concentration-dependent manner. Incubation with CRE induced a significant suppression of IL-1β and IFN-γ-induced nitric oxide (NO) production, a finding which correlated well with reduced levels of the iNOS mRNA and protein. The molecular mechanism by which CRE inhibited iNOS gene expression appeared to involve the inhibition of NF-κB activation. The IL-1β and IFN-γ-stimulated RIN cells showed increases in NF-κB binding activity and p65 subunit levels in nucleus, and IκBα degradation in cytosol compared to unstimulated cells. Furthermore, the protective effects of CRE were verified via the observation of reduced NO generation and iNOS expression, and normal insulin-secretion responses to glucose in IL-1β and IFN-γ-treated islets.

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“…Protein samples were separated by SDS-PAGE and transferred to nitrocellulose membranes (Amersham Pharmacia Biotech) under semidry transfer conditions as previously described (43,44). Ab dilutions were: rabbit antimouse COX-2, 1/1000Ј rabbit anti-mouse iNOS, 1/1000; and HRP-conjugated donkey anti-rabbit, 1/7000.…”

Section: Western Blot Analysismentioning

confidence: 99%

Regulation of Cyclooxygenase-2 Expression by Macrophages in Response to Double-Stranded RNA and Viral Infection

Steer¹,

Moran

Maggi³

et al. 2003

The Journal of Immunology

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In this study the regulation of macrophage expression of cyclooxygenase-2 (COX-2) in response to dsRNA and virus infection was examined. Treatment of RAW 264.7 macrophages with dsRNA results in COX-2 mRNA accumulation and protein expression and the production of PGE2. Similar to dsRNA, encephalomyocarditis virus (EMCV) infection of RAW 264.7 cells stimulates COX-2 expression and PGE2 accumulation. The dsRNA-dependent protein kinase (PKR), which has been shown to participate in the regulation of gene expression in response to dsRNA and virus infection, does not appear to participate in the regulation of COX-2 expression by macrophages. Expression of dominant negative mutants of PKR in RAW 264.7 cells fails to attenuate dsRNA- and EMCV-induced COX-2 expression or PGE2 production. Furthermore, dsRNA and EMCV stimulate COX-2 expression and PGE2 accumulation to similar levels in macrophages isolated from wild-type and PKR-deficient mice. Recently, a novel PKR-independent role for the calcium-independent phospholipase A2 (iPLA2) in the regulation of inducible NO synthase expression by macrophages in response to virus infection has been identified. The selective iPLA2 suicide substrate inhibitor bromoenol lactone prevents dsRNA- and EMCV-stimulated inducible NO synthase expression; however, bromoenol lactone does not attenuate dsRNA- or EMCV-induced COX-2 expression by macrophages. In contrast, inhibition of NF-κB activation prevents dsRNA-stimulated COX-2 expression and PGE2 accumulation by macrophages. These findings indicate that virus infection and treatment with dsRNA stimulate COX-2 expression by a mechanism that requires the activation of NF-κB and that is independent of PKR or iPLA2 activation.

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Interferon-γ Increases the Sensitivity of Islets of Langerhans for Inducible Nitric-oxide Synthase Expression Induced by Interleukin 1

Cited by 153 publications

References 37 publications

Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells

Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells

Coptidis rhizoma extract protects against cytokine-induced death of pancreatic β-cells through suppression of NF-κ B activation

Regulation of Cyclooxygenase-2 Expression by Macrophages in Response to Double-Stranded RNA and Viral Infection

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