Cooperativity between oxidants and tumor necrosis factor in the activationof nuclear factor (NF)-kappa B - Requirement of Ras/mitogen-activated protein kinases in the activation of NF-kappa B by oxidants
Ymw. Janssen-heininger et al., Cooperativity between oxidants and tumor necrosis factor in the activationof nuclear factor (NF)-kappa B - Requirement of Ras/mitogen-activated protein kinases in the activation of NF-kappa B by oxidants, AM J RESP C, 20(5), 1999, pp. 942-952
Citations number
43
Categorie Soggetti
da verificare
Journal title
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
The transcription factor nuclear factor (NF)-kappa B is activated by oxidat
ive stress or cytokines and is critical to the activation of inflammatory g
enes. Here, we report that hydrogen peroxide or 3-morpholinosydnonimine, wh
ich simultaneously releases nitric oxide and superoxide, synergize with the
cytokine tumor necrosis factor (TNF)-alpha to activate NF-kappa B in rat l
ung epithelial cells, suggesting that signaling pathways elicited by reacti
ve oxygen species (ROS)/reactive nitrogen species (RNS) are different from
TNF-induced signaling. These findings were substantiated by observations th
at levels of I kappa B-alpha did not change after exposure to ROS/RNS, wher
eas a rapid depletion of I kappa B-alpha was observed in cells exposed to T
NF. In addition, the proteosome inhibitor MG132 did not affect activation o
f NF-kappa B by ROS/RNS, whereas it abolished the TNF response. Transfectio
n of a dominant negative Pas construct prevented the activation of NF-kappa
B by ROS/RNS, demonstrating the requirement for Ras in the activation of N
F-kappa B by oxidants. In contrast, TNF activated NF-kappa B in a Ras-indep
endent fashion. Evaluation of members of the mitogen-activated protein kina
se (MAPK) family as downstream effecters of Ras revealed the requirement of
MAPK/ extracellular-regulated kinase (ERK) kinase kinase (MEKK)1 and c-Jun
N-terminal kinases in the induction of NF-kappa B by both oxidants and TNF
, whereas the MEK-ERK pathway negatively regulates NF-kappa B, Our findings
demonstrate that cytokines and oxidants cooperate in the activation of tra
nscription actors through distinct pathways, and suggest that anti-inflamma
tory and antioxidant therapies may be required in concert to prevent the ac
tivation of NF-kappa B-regulated genes important in the development of infl
ammatory diseases.