Nucling, a novel protein associated with NF-κB, regulates endotoxin-induced apoptosis in vivo.
Nucling is a proapoptotic protein that regulates the apoptosome and nuclear factor-kappa B (NF-κB) signalling pathways. Strong stimuli, such as Gram-negative bacterial lipopolysaccharide (LPS), induce the simultaneous secretion of cytokines following the activation of NF-κB. Proinflammatory cytokines can induce liver damage through several mechanisms such as increases in oxidative stress and apoptotic reactions leading to tissue necrosis. Herein, we show that Nucling-knockout (KO) mice are resistant to LPS that consistently caused mortality in wild-type (WT) counterparts. Although serum levels of cytokines such as tumour necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 did not differ significantly between WT and Nucling-KO mice after the LPS challenge, hepatocytes of Nucling-KO mice were refractory to LPS- or TNF-α-induced cell death. These results were consistent with the decreased expression of proapoptotic proteins including apoptosis-inducing factor and cleaved form of poly (ADP-ribose) polymerase and terminal deoxynucleotidyl transferase dUTP nick end-labelling positive cells in the liver of Nucling-KO mice after the administration of a lethal dose of LPS. Moreover, the upregulation of NF-κB-regulated anti-apoptotic molecules including cellular inhibitor of apoptosis (cIAP) 1 and cIAP2 was observed in the liver of Nucling-KO mice after LPS treatment. These findings indicate that the Nucling deficiency leads to resistance to apoptosis in liver. We propose that Nucling is important for the induction of apoptosis in cells damaged by cytotoxic stressors through the NF-κB signalling pathway.
Division of Enzyme Pathophysiology, The Institute for Enzyme Research (KOSOKEN), The University of Tokushima, Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
Sun Mi
SM
Kim
Takashi
T
Sakai
Huy Van
HV
Dang
Nam Hoang
NH
Tran
Koji
K
Ono
Kazunori
K
Ishimura
Kiyoshi
K
Fukui
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D060467:Disease Resistance; D015536:Down-Regulation; D004731:Endotoxins / Q000633:toxicity; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007728:Kupffer Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D012772:Shock, Septic / Q000097:blood / Q000276:immunology / Q000378:metabolism* / Q000401:mortality; D015398:Signal Transduction; D013047:Specific Pathogen-Free Organisms; D016019:Survival Analysis; D015996:Survival Rate; D015854:Up-Regulation
D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D004731:Endotoxins; D008565:Membrane Proteins; D016328:NF-kappa B; C483107:Uaca protein, mouse; C044101:endotoxin, Escherichia coli