Portal de Periódicos da CAPES

Protection of NIT-1 Pancreatic β-Cells From Immune Attack by Inhibition of NF-κB

1997; Elsevier BV; Volume: 10; Issue: 3 Linguagem: Inglês

10.1006/jaut.1997.0133

1095-9157

Leigh A. Stephens, Helen E. Thomas, Thomas W. H. Kay,

NF-κB Signaling Pathways

We have recently observed that inhibition of NF-|gkB 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)β-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-|gkB on class I major histocompatibility complex (MHC) protein expression in NIT-1 cells and shown that inhibition of NF-|gkB activation decreased basal and TNF-induced class I MHC levels. Although inducible nitric oxide synthase (iNOS) may also be inhibited by inhibition of NF-|gkB, this could not be demonstrated in NIT-1/Δsp cells because wild-type NIT-1 cells express very little iNOS. When NIT-1/Δsp12 cells, expressing high levels of the NF-|gkB inhibitor, are transplanted into immunodeficient NOD/scid mice, tumori-genesis 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/Δsp12 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/Δsp12 cells were not protected from killing by T cells from mice previously primed with NIT-1 cells. In conclusion, inhibition of NF-|gkB is likely to suppress several different pathways of immune-mediated cell death in β-cells and protects NIT-1 cells from immune attack by diabetogenic T cells in vivo. Inhibition of NF-|gkB is a potentially effective strategy for protection of pancreatic β-cells in autoimmune diabetes.