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Complete Protection Against Interleukin-1ß–Induced Functional Suppression and Cytokine-Mediated Cytotoxicity in Rat Pancreatic Islets In Vitro Using an Interleukin-1 Cytokine Trap

From the Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden

Address correspondence and reprint requests to Dr. Tobias Rydgren, Department of Medical Cell Biology, Biomedicum, P.O. Box 571, SE-751 23 Uppsala, Sweden. E-mail: tobias.rydgren{at}medcellbiol.uu.se

Abbreviations: IFN, interferon; IL, interleukin; IL-1Ra, IL-1 receptor antagonist; TNF, tumor necrosis factor

Cytokines, particularly interleukin (IL)-1ß, have been postulated to cause ß-cell destruction in type 1 diabetes. We tested the efficacy of an IL-1 cytokine trap in counteraction of suppressive and toxic effects after exposure of rat pancreatic islets in vitro to IL-1ß. The IL-1 cytokine trap used herein comprised extracellular domains of the IL-1 receptor accessory protein and the human IL-1 receptor 1 arranged inline and fused to the Fc portion of human IgG1. Groups of isolated rat pancreatic islets were maintained in medium culture with or without IL-1ß (150 pmol/l) for 48 h in the absence or presence of the IL-1 trap at 1-, 10-, or 100-fold excess the molar concentration of the cytokine. IL-1ß alone induced a strong inhibition of insulin secretion and glucose oxidation rate and a marked increase in medium nitrite accumulation as an indicator of nitric oxide generation. When the IL-1 trap was used at a ratio 10:1 or 100:1, a complete protection against these effects were observed. Moreover, the IL-1 trap (100:1) blocked the increased islet cell death seen in islets treated with a combination of IL-1ß + tumor necrosis factor- + interferon- as well as functional suppression induced by the cytokine combination. In conclusion, we show that addition of an IL-1 trap can protect rat pancreatic islets in vitro against noxious effects induced by IL-1ß. Exploring the IL-1 trap in relevant animal models of type 1 diabetes represents an interesting future intervention strategy.

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