Evidence that reactive oxygen species do not mediate NF-kappaB activation.
It has been postulated that reactive oxygen species (ROS) may act as second messengers leading to nuclear factor (NF)-kappaB activation. This hypothesis is mainly based on the findings that N-acetyl-L-cysteine (NAC) and pyrrolidine dithiocarbamate (PDTC), compounds recognized as potential antioxidants, can inhibit NF-kappaB activation in a wide variety of cell types. Here we reveal that both NAC and PDTC inhibit NF-kappaB activation independently of antioxidative function. NAC selectively blocks tumor necrosis factor (TNF)-induced signaling by lowering the affinity of receptor to TNF. PDTC inhibits the IkappaB-ubiquitin ligase activity in the cell-free system where extracellular stimuli-regulated ROS production does not occur. Furthermore, we present evidence that endogenous ROS produced through Rac/NADPH oxidase do not mediate NF-kappaB signaling, but instead lower the magnitude of its activation.
Hayakawa
Makio
M
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Tokyo 192-0392, Japan.
Miyashita
Hiroshi
H
Sakamoto
Isao
I
Kitagawa
Masatoshi
M
Tanaka
Hirofumi
H
Yasuda
Hideyo
H
Karin
Michael
M
Kikugawa
Kiyomi
K
D000111:Acetylcysteine / Q000494:pharmacology; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013859:Thiocarbamates / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology
D017931:DNA Primers; D016328:NF-kappa B; D011759:Pyrrolidines; D017382:Reactive Oxygen Species; D018124:Receptors, Tumor Necrosis Factor; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; C020972:pyrrolidine dithiocarbamic acid; D000111:Acetylcysteine