NF-kappaB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death.
NF-kappaB downregulates tumor necrosis factor (TNF)-induced c-Jun N-terminal kinase (JNK) activation that promotes cell death, but the mechanism is not yet fully understood. By using murine embryonic fibroblasts (MEFs) that are deficient in TNF receptor-associated factor (TRAF) 2 and TRAF5 (DKO) or p65 NF-kappaB subunit (p65KO), we demonstrate here that TNF stimulation leads to accumulation of reactive oxygen species (ROS), which is essential for prolonged mitogen-activated protein kinase (MAPK) activation and cell death. Interestingly, dying cells show necrotic as well as apoptotic morphological changes as assessed by electron microscopy and flow cytometry, and necrotic, but not apoptotic, cell death is substantially inhibited by antioxidant. Importantly, TNF does not induce ROS accumulation or prolonged MAPK activation in wild-type MEFs, indicating that TRAF-mediated NF-kappaB activation normally suppresses the TNF-induced ROS accumulation that subsequently induces prolonged MAPK activation and necrotic cell death
Sakon
Sachiko
S
Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, Japan.
Xue
Xin
X
Takekawa
Mutsuhiro
M
Sasazuki
Tomonari
T
Okazaki
Tatsuma
T
Kojima
Yuko
Y
Piao
Jian-Hu
JH
Yagita
Hideo
H
Okumura
Ko
K
Doi
Takahiro
T
Nakano
Hiroyasu
H
D000818:Animals; D016923:Cell Death; D005978:Glutathione / Q000378:metabolism; D051379:Mice; D008854:Microscopy, Electron; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology*; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000502:physiology
D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D009249:NADP; D020928:Mitogen-Activated Protein Kinases; D005978:Glutathione