Perturbations in nuclear factor-[kappa]B or c-Jun N-terminal kinase pathways in pancreatic beta cells confer susceptibility to cytokine-induced cell death

SummaryPro-inflammatory cytokines have been implicated in the death of pancreatic beta cells leading to type 1 diabetes. NIT-1 cells are an insulinoma cell line derived from mice expressing the SV40 large T antigen. These cells are a useful tool in analysis of beta cell death. NIT-1 cells are highly susceptible to caspase-dependent apoptosis induced by TNF-α alone. Primary islets are not susceptible to cell death induced by TNF-α alone; however, they are killed by TNF-α and IFN-γ in a nitric oxide-dependent manner. We examined signal transduction in NIT-1 cells in response to cytokines to determine the mechanism for TNF-α-induced apoptosis. We found that NIT-1 cells are defective in the activation of nuclear factor-κB (NFκB) as a result of functionally deficient RelA activity, because overexpression of RelA protected NIT-1 cells from apoptosis. TNF-α also did not induce phosphorylation of c-Jun N-terminal kinase in NIT-1 cells. Together, these defects prevent expression of anti-apoptotic genes in NIT-1 cells and make them susceptible to TNF-α. To determine whether similar defects in primary beta cells would induce the same effect, we examined TNF-α-induced apoptosis in islets isolated from mice deficient in NFκB p50. These islets were as susceptible as wild-type islets to TNF-α and IFN-γ-induced cell death. In contrast to wild-type islets, cell death was not prevented by inhibition of nitric oxide in p50-deficient islets. Blocking NFκB has been proposed as a mechanism for protection of beta cells from cytokine-induced cell death in vivo. Our results suggest that this would make beta cells equally or more sensitive to cytokines.