Complete protection against interleukin-1beta-induced functional suppression and cytokine-mediated cytotoxicity in rat pancreatic islets in vitro using an interleukin-1 cytokine trap.
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.
Rydgren
Tobias
T
Department of Medical Cell Biology, Biomedicum, Uppsala University, P.O. Box 571, SE-751 23 Uppsala, Sweden. tobias.rydgren@medcellbiol.uu.se
Bengtsson
Daniel
D
Sandler
Stellan
S
D000818:Animals; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000502:physiology*; D005434:Flow Cytometry; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007375:Interleukin-1 / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D008297:Male; D009573:Nitrites / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D016207:Cytokines; D007328:Insulin; D007375:Interleukin-1; D009573:Nitrites; D005947:Glucose