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Perturbations in nuclear factor‐κB or c‐Jun N‐terminal kinase pathways in pancreatic beta cells confer susceptibility to cytokine‐induced cell death
Author(s) -
Thomas Helen E,
Angstetra Eveline,
Fernandes Rochelle V,
Mariana Lina,
Irawaty Windy,
Jamieson Emma L,
Dudek Nadine L,
Kay Thomas W
Publication year - 2006
Publication title -
immunology and cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.999
H-Index - 104
eISSN - 1440-1711
pISSN - 0818-9641
DOI - 10.1111/j.1440-1711.2005.01397.x
Subject(s) - c jun , cytokine , microbiology and biotechnology , kinase , terminal (telecommunication) , chemistry , beta (programming language) , biology , cancer research , transcription factor , immunology , biochemistry , gene , telecommunications , computer science , programming language
Pro‐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.