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B Activation by TNF Via the Activation of p38 Mitogen-Activated Protein Kinase1
Department of Biochemistry, Trinity College, Dublin, Ireland
The transcription factor NF-
B is a central mediator of altered
gene expression during inflammation, and is implicated in a number of
pathologies, including cancer, atherosclerosis, and viral infection. We
report in this study that vitamin C inhibits the activation of NF-B
by multiple stimuli, including IL-1 and TNF in the endothelial cell
line ECV304 and in primary HUVECs. The induction of a NF-B-dependent
gene, IL-8, by TNF was also inhibited. The effect requires millimolar
concentrations of vitamin C, which occur intracellularly in vivo,
particularly during inflammation. Vitamin C was not toxic to cells, did
not inhibit another inducible transcription factor, STAT1, and had no
effect on the DNA binding of NF-B. Inhibition by vitamin C was not
simply an antioxidant effect, because redox-insensitive pathways to
NF-B were also blocked. Vitamin C was shown to block IL-1- and
TNF-mediated degradation and phosphorylation of I-B
(inhibitory
protein that dissociates from NF-B), due to inhibition of I-B
kinase (IKK) activation. Inhibition of TNF-driven IKK activation was
mediated by p38 mitogen-activated protein kinase, because treatment of
cells with vitamin C led to a rapid and sustained activation of p38,
and the specific p38 inhibitor SB203580 reversed the inhibitory effect
of vitamin C on IKK activity, I-B phosphorylation, and NF-B
activation. The results identify p38 as an intracellular target for
high dose vitamin C.
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