Vitamin C suppresses TNFα-induced NFκB activation by inhibiting IκBα phosphorylation Journal Article

Authors: Cárcamo, J. M.; Pedraza, A.; Bórquez-Ojeda, O.; Golde, D. W.
Article Title: Vitamin C suppresses TNFα-induced NFκB activation by inhibiting IκBα phosphorylation
Abstract: Extracellular stimuli signal for activation of the transcription factor NFκB, leading to gene expression regulating processes involved in immune responses, inflammation, and cell survival. Tumor necrosis factor-α (TNFα) activates NFκB via a well-defined kinase pathways involving NFκB-inducing kinase (NIK), which activates downstream multisubunit IκB kinases (IKK). IKK in turn phosphorylates IκB, the central regulator of NFκB function. We found that intracellular vitamin C inhibits TNFα-induced activation of NFκB in human cell lines (HeLa, monocytic U937, myeloid leukemia HL-60, and breast MCF7) and primary endothelial cells (HUVEC) in a dose-dependent manner. Vitamin C is an important antioxidant, and most cells accumulate ascorbic acid (AA) intracellularly by transporting the oxidized form of the vitamin, dehydroascorbic acid (DHA). Because ascorbic acid is a strong pro-oxidant in the presence of transition metals in vitro, we loaded cells with vitamin C by incubating them with DHA. Vitamin C-loaded cells showed significantly decreased TNFα-induced nuclear translocation of NFκB, NFκB-dependent reporter transcription, and IκBα phosphorylation. Our data point to a mechanism of vitamin C suppression of NFκB activation by inhibiting TNFα-induced activation of NIK and IKKβ kinases independent of p38 MAP kinase. These results suggest that intracellular vitamin C can influence inflammatory, neoplastic, and apoptotic processes via inhibition of NFκB activation.
Keywords: signal transduction; mitogen activated protein kinase; protein phosphorylation; human cell; dose response; cell survival; enzyme inhibition; cell line; inflammation; immunoglobulin enhancer binding protein; genetic transcription; enzyme activation; hela cell; hela cells; phosphorylation; endothelium cell; gene expression regulation; gene activation; immunology; immune response; tumor necrosis factor alpha; tumor necrosis factor-alpha; tumors; protein-serine-threonine kinases; anti-inflammatory agents, non-steroidal; nf-kappa b; reporter gene; active transport, cell nucleus; antioxidant; antioxidants; ascorbic acid; cell nucleus; cell transport; mitogen-activated protein kinases; cell strain mcf 7; oxidation; dehydroascorbic acid; enzymes; synaptophysin; cell strain u937; u937 cells; cells; i-kappa b proteins; i-kappa b kinase; vitamins; i kappa b alpha; p38 mitogen-activated protein kinases; trans-activation (genetics); hl-60 cells; cell strain hl 60; humans; human; priority journal; article; mink cell focus-forming virus; phosphoryaltion; transition metals
Journal Title: Biochemistry
Volume: 41
Issue: 43
ISSN: 0006-2960
Publisher: American Chemical Society  
Date Published: 2002-10-29
Start Page: 12995
End Page: 13002
Language: English
DOI: 10.1021/bi0263210
PUBMED: 12390026
PROVIDER: scopus
Notes: Export Date: 14 November 2014 -- Source: Scopus
Citation Impact
MSK Authors
  1. David Golde
    127 Golde
  2. Juan O Carcamo
    31 Carcamo
  3. Alicia Maria Pedraza
    20 Pedraza