Caspase-1 is not required for type 1 diabetes in the NOD mouse.

Abstract

Interleukin (IL)-1 beta and IL-18 are two cytokines associated with the immunopathogenesis of diabetes in NOD mice. Both of these cytokines are cleaved by caspase-1 to their biologically active forms. IL-1 is a proinflammatory cytokine linked to beta-cell damage, and IL-18 stimulates production of interferon (IFN)gamma in synergy with IL-12. To examine the effects produced by caspase-1 deficiency on diabetes development in NOD/Lt mice, a disrupted Casp1 gene was introduced by a speed congenic technique. Casp1(-/-) bone marrow-derived macrophages stimulated with lipopolysaccharide produced no detectable IL-18, fourfold lower IL-1 beta, and 20-30% less IL-1 alpha than macrophages from wild-type Casp1(+/+) or Casp1(+/-) controls. Unexpectedly, despite reduced IL-1 and IL-18, there was no change in the rate of diabetes or in total incidence as compared with that in wild-type NOD mice. IL-1 reportedly makes an important pathological contribution in the multidose streptozotocin model of diabetes; however, there was no difference in sensitivity to streptozotocin between NOD mice and NOD.Casp1(-/-) mice at 40 mg/kg body wt or at 25 mg/kg body wt dosage levels. These findings show that caspase-1 processing of IL-1 beta and IL-18 is not absolutely required for mediation of spontaneous or chemically induced diabetes pathogenesis in the NOD mouse.