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c‐Jun N‐terminal kinase inhibits TNFα‐induced NF‐κB activation through endosomal Nox1 in vascular smooth muscle cells (1096.4)
Author(s) -
Choi Hyehun,
Lamb Fred
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1096.4
Subject(s) - nox1 , microbiology and biotechnology , nadph oxidase , chemistry , tumor necrosis factor alpha , vascular smooth muscle , nf κb , endocytosis , apoptosis , signal transduction , kinase , biology , reactive oxygen species , cell , endocrinology , biochemistry , smooth muscle
Tumor necrosis factor‐α (TNFα), a pro‐inflammatory cytokine, can cause either vascular smooth muscle cell (VSMC) apoptosis (JNK‐dependent) or proliferation (NF‐κB‐dependent). We hypothesized that JNK modifies NADPH oxidase (Nox1)‐dependent NF‐κB stimulation by TNFα in VSMC. We quantified the impact of siRNA targeting JNK1 or 2 on TNFα dependent NF‐κB activation using an adenoviral reporter construct in cultured aortic VSMC from wildtype (WT) or Nox1 knockout (Nox1KO) mice. NF‐κB activation was potentiated 1.5 + 0.5 fold (n=6) by siRNA targeting JNK1 and 2 in WT cells, however, there was no effect on NF‐κB activation in Nox1KO cells (0.9 + 0.1 fold, n=4). NF‐κB activation was endocytosis‐dependent as it was blocked by dominant‐negative dynamin (Ad‐DynK44A, 61% reduction, n=4). JNK inhibition with SP600125 did not alter endocytosis of dextran‐conjugated Texas Red. Endosomal ROS production is required for NF‐κB activation by TNFα in VSMC. JNK regulates NF‐κB activation either at the level of Nox1 activation or at a step downstream of ROS. Reduction of NF‐κB activation by JNK may tip the balance of signaling to favor cell death over proliferation. Grant Funding Source : Supported by American Heart Association