Complete protection against interleukin-1beta-induced functional suppression and cytokine-mediated cytotoxicity in rat pancreatic islets in vitro using an interleukin-1 cytokine trap.

Abstract

Cytokines, particularly interleukin (IL)-1beta, have been postulated to cause beta-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-1beta. 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-1beta (150 pmol/l) for 48 hours in the absence or presence of the IL-1 trap at 1-, 10-, or 100-fold excess the molar concentration of the cytokine. IL-1beta 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-1beta + tumor necrosis factor-alpha + interferon-gamma 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-1beta. Exploring the IL-1 trap in relevant animal models of type 1 diabetes represents an interesting future intervention strategy.