Caspase-1 is not required for type 1 diabetes in the NOD mouse.
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.
Schott
William H
WH
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Haskell
Bradford D
BD
Tse
Hubert M
HM
Milton
Martha J
MJ
Piganelli
Jon D
JD
Choisy-Rossi
Caroline Morgane
CM
Reifsnyder
Peter C
PC
Chervonsky
Alexander V
AV
Leiter
Edward H
EH
D000818:Animals; D020170:Caspase 1 / Q000172:deficiency / Q000235:genetics*; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000503:physiopathology*; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D015994:Incidence; D007375:Interleukin-1 / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D007700:Kinetics; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D012727:Sex Characteristics; D013045:Species Specificity; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D007375:Interleukin-1; D020382:Interleukin-18; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D020170:Caspase 1