Protection of NIT-1 pancreatic beta-cells from immune attack by inhibition of NF-kappaB.
We have recently observed that inhibition of NF-kappaB in NIT-1 insulinoma cells protects them from tumour necrosis factor (TNF)-induced cell death in vitro, possibly because expression of interleukin-1 (IL-1)beta-converting enzyme (ICE), a member of the cysteine protease pathway of cell death, is decreased. In the current study we have examined the effect of the same inhibitor of NF-kappaB on class I major histocompatibility complex (MHC) protein expression in NIT-1 cells and shown that inhibition of NF-kappaB activation decreased basal and TNF-induced class I MHC levels. Although inducible nitric oxide synthase (iNOS) may also be inhibited by inhibition of NF-kappaB, this could not be demonstrated in NIT-1/delta sp cells because wild-type NIT-1 cells express very little iNOS. When NIT-1/delta sp12 cells, expressing high levels of the NF-kappaB inhibitor, are transplanted into immunodeficient NOD/scid mice, tumorigenesis and death by hypoglycemia proceed similarly to untransfected NIT-1 cells. Untransfected NIT-1 cells were killed by co-transfer of splenic T cells from diabetic but not non-diabetic NOD mice. NIT-1/delta sp12 cells were protected from killing in vivo by T cells from diabetic mice, in that tumours developed in four out of five mice and the kinetics of tumour development were not significantly delayed. NIT-1/delta sp12 cells were not protected from killing by T cells from mice previously primed with NIT-1 cells. In conclusion, inhibition of NF-kappaB is likely to suppress several different pathways of immune-mediated cell death in beta-cells and protects NIT-1 cells from immune attack by diabetogenic T cells in vivo. Inhibition of NF-kappaB is a potentially effective strategy for protection of pancreatic beta-cells in autoimmune diabetes.
Stephens
L A
LA
Burnet Clinical Research Unit, Walter and Eliza Hall Institute of Medical Research, Victoria, Australia.
Thomas
H E
HE
Kay
T W
TW
D019264:Adoptive Transfer; D000818:Animals; D016923:Cell Death / Q000276:immunology; D002461:Cell Line, Transformed; D003602:Cytotoxicity, Immunologic; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000517:prevention & control; D005260:Female; D006183:H-2 Antigens / Q000096:biosynthesis; D007515:Islets of Langerhans / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000637:transplantation; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000633:toxicity
D006183:H-2 Antigens; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D019001:Nitric Oxide Synthase