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

Abstract

Cytokines, particularly interleukin (IL)-1β, have been postulated to cause β-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-1β. 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-1β (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-1β 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-1β + tumor necrosis factor-α + interferon-γ 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-1β. Exploring the IL-1 trap in relevant animal models of type 1 diabetes represents an interesting future intervention strategy.