title: LIGHT/IFN-γ triggers β cells apoptosis via NF-κB/Bcl2-dependent mitochondrial pathway.
abstract: LIGHT recruits and activates naive T cells in the islets at the onset of diabetes. IFN-γ secreted by activated T lymphocytes is involved in beta cell apoptosis. However, whether LIGHT sensitizes IFNγ-induced beta cells destruction remains unclear. In this study, we used the murine beta cell line MIN6 and primary islet cells as models for investigating the underlying cellular mechanisms involved in LIGHT/IFNγ - induced pancreatic beta cell destruction. LIGHT and IFN-γ synergistically reduced MIN6 and primary islet cells viability; decreased cell viability was due to apoptosis, as demonstrated by a significant increase in Annexin V(+) cell percentage, detected by flow cytometry. In addition to marked increases in cytochrome c release and NF-κB activation, the combination of LIGHT and IFN-γ caused an obvious decrease in expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL, but an increase in expression of the pro-apoptotic proteins Bak and Bax in MIN6 cells. Accordingly, LIGHT deficiency led to a decrease in NF-κB activation and Bak expression, and peri-insulitis in non-obese diabetes mice. Inhibition of NF-κB activation with the specific NF-κB inhibitor, PDTC (pyrrolidine dithiocarbamate), reversed Bcl-xL down-regulation and Bax up-regulation, and led to a significant increase in LIGHT- and IFN-γ-treated cell viability. Moreover, cleaved caspase-9, -3, and PARP (poly (ADP-ribose) polymerase) were observed after LIGHT and IFN-γ treatment. Pretreatment with caspase inhibitors remarkably attenuated LIGHT- and IFNγ-induced cell apoptosis. Taken together, our results indicate that LIGHT signalling pathway combined with IFN-γ induces beta cells apoptosis via an NF-κB/Bcl2-dependent mitochondrial pathway.
authors.affiliation: Department of Nephrology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Quan-You
authors.initials: QY
authors.lastname: Zheng
authors.affiliation: Department of Nephrology, Southwest Hospital, Third Military Medical University, Chongqing, China.|Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmacy and Biosciences, University of South China, Hengyang, China.|Department of Immunology, School of Basic Medical Sciences, Third Military Medical University, Chongqing, China.
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Cao
authors.affiliation: Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmacy and Biosciences, University of South China, Hengyang, China.
authors.forename: Xiao-Bo
authors.initials: XB
authors.lastname: Hu
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Third Military Medical University, Chongqing, China.
authors.forename: Gui-Qing
authors.initials: GQ
authors.lastname: Li
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Third Military Medical University, Chongqing, China.
authors.forename: Shi-Fang
authors.initials: SF
authors.lastname: Dong
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Third Military Medical University, Chongqing, China.
authors.forename: Gui-Lian
authors.initials: GL
authors.lastname: Xu
authors.affiliation: Department of Nephrology, Southwest Hospital, Third Military Medical University, Chongqing, China. zhkq2004@163.com.
authors.forename: Ke-Qin
authors.initials: KQ
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D016688:Mice, Inbred NOD; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013312:Stress, Physiological / Q000187:drug effects; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000494:pharmacology*
chemical_list: D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D007371:Interferon-gamma; D045304:Cytochromes c; D053148:Caspase 3; D053453:Caspase 9
keywords: LIGHT; NF-κB; apoptosis; mitochondrial stress; pancreatic beta cell