TNF-α and IFN-γ potentiate the deleterious effects of IL-1β on mouse pancreatic islets mainly via generation of nitric oxide

Ćetković-Cvrlje, Marina; Eizirik, Décio L.

doi:10.1016/1043-4666(94)90064-7

Cited by 168 publications

(127 citation statements)

References 28 publications

Supporting

Mentioning

118

Contrasting

Order By: Relevance

“…This indicates that the multilayers of the polysaccharides were deposited non-covalently on to the cell surfaces without perturbing cellular physiology or compromising cell survival. Pro-inflammatory cytokines, including IFN-γ, TNF-α and IL-1β, are major products of activated effective T cells and macrophages, and are known to be damaging to pancreatic islets via apoptosis induction [41]. In this study, we found that the nano-coating also rendered the islets less susceptible to cytokine-and complement-induced apoptosis (Fig.…”

Section: Discussionsupporting

confidence: 52%

Nano-scale encapsulation enhances allograft survival and function of islets transplanted in a mouse model of diabetes

et al. 2012

View full text Add to dashboard Cite

Aims/hypothesis The success of islet transplantation as a treatment for type 1 diabetes is currently hampered by post-transplantation loss of functional islets through adverse immune and non-immune reactions. We aimed to test whether early islet loss can be limited and transplant survival improved by the application of conformal nano-coating layers to islets. Methods Our novel coating protocol used alternate layers of phosphorylcholine-derived polysaccharides (chitosan or chondroitin-4-sulphate) and alginate as coating materials, with the binding based on electrostatic complexation. The in vitro function of encapsulated mouse islets was studied by analysing islet secretory function and cell viability. The in vivo function was evaluated using syngeneic and allogeneic transplantation in the streptozotocin-induced mouse model of diabetes. Results Nano-scale encapsulated islets retained appropriate islet secretory function in vitro and were less susceptible to complement-and cytokine-induced apoptosis than nonencapsulated control islets. In in vivo experiments using a syngeneic mouse transplantation model, no deleterious responses to the coatings were observed in host animals, and the encapsulated islet grafts were effective in reversing hyperglycaemia. Allo-transplantation of the nano-coated islets resulted in preserved islet function post-implantation in five of seven mice throughout the 1 month monitoring period. Conclusions/interpretation Nano-scale encapsulation offers localised immune protection for implanted islets, and may be able to limit early allograft loss and extend survival of transplanted islets. This versatile coating scheme has the potential to be integrated with tolerance induction mechanisms, thereby achieving long-term success in islet transplantation.

show abstract

Section: Discussionsupporting

confidence: 52%

Nano-scale encapsulation enhances allograft survival and function of islets transplanted in a mouse model of diabetes

et al. 2012

View full text Add to dashboard Cite

show abstract

“…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%

“…NF-B regulates the expressions of multiple proinflammatory genes that contribute to islet destruction, including Fas, iNOS, and cyclooxygenase-2 (Cetkovic-Cvrlje and Eizirik, 1994;Sorli et al, 1998;Darville and Eizirik, 2001). In addition, the promoters of other proinflammatory genes induced in -cells, including chemokines and adhesion molecules, also possess binding elements for NF-B (May and Ghosh, 1998).…”

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%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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.

show abstract

“…cRNA was prepared from islets isolated from nondiabetic-prone BALB/c mice or diabetic-prone NOD mice. For each islet preparation, islets were either left untreated or stimulated with IL-1␤ or TNF-␣ for 1 h. These cytokines were chosen based on their established roles in inducing ␤-cell apoptosis both in vitro (21,33,34) and in vivo (35)(36)(37).…”

Section: ␤-Cells Have An Inducible Antiapoptotic Responsementioning

confidence: 99%

Nuclear Factor-κB Regulates β-Cell Death

et al. 2006

View full text Add to dashboard Cite

Apoptotic ␤-cell death is central to the pathogenesis of type 1 diabetes and may be important in islet graft rejection. Despite this, genetic control of ␤-cell apoptosis is only poorly understood. We report that inhibition of gene transcription sensitized ␤-cells to tumor necrosis factor (TNF)-␣-induced apoptosis, indicating the presence of a regulated antiapoptotic response. Using oligonucleotide microarrays and real-time PCR, we identified TNFAIP3/A20 as the most highly regulated antiapoptotic gene expressed in cytokinestimulated human and mouse islets. Cytokine induction of A20 mRNA in primary islets and insulinoma cells was rapid and observed within 1 h, consistent with A20 being an immediate early response gene in ␤-cells. Regulation of A20 was nuclear factor-B (NF-B)-dependent, two NF-B sites within the A20 promoter were found to be necessary and sufficient for A20 expression in ␤-cells. Activation of NF-B by TNF receptor-associated factor (TRAF) 2, TRAF6, NF-B-inducing kinase, or protein kinase D, which transduce signals downstream of Toll-like receptors, TNF receptors, and free radicals, respectively, were all potent activators of the A20 promoter. Moreover, A20 expression was induced in transplanted islets in vivo. Finally, A20 expression was sufficient to protect ␤-cells from TNFinduced apoptosis. These data demonstrate that A20 is the cardinal antiapoptotic gene in ␤-cells. Further, A20 expression is NF-B dependent, thus linking islet proinflammatory gene responses with protection from apoptosis.

show abstract

TNF-α and IFN-γ potentiate the deleterious effects of IL-1β on mouse pancreatic islets mainly via generation of nitric oxide

Cited by 168 publications

References 28 publications

Nano-scale encapsulation enhances allograft survival and function of islets transplanted in a mouse model of diabetes

Nano-scale encapsulation enhances allograft survival and function of islets transplanted in a mouse model of diabetes

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

Nuclear Factor-κB Regulates β-Cell Death

Contact Info

Product

Resources

About