期刊
BIOCHEMICAL PHARMACOLOGY
卷 81, 期 4, 页码 534-543出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2010.12.004
关键词
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资金
- Spanish Ministerio de Ciencia e Innovacion [SAF2006-01475, SAF2009-06939]
- European Union
Nuclear factor (NF)-kappa B is a ubiquitously expressed transcription factor controlling the expression of numerous genes involved in inflammation. The aim of this study was to evaluate whether activation of the peroxisome proliferator-activated receptor (PPAR) beta/delta prevented TNF-alpha-induced NF-kappa B activation in human HaCaT keratinocytes and, if so, to determine the mechanism involved. The PPAR beta/delta agonist GW501516 inhibited the increase caused by TNF-alpha in the mRNA levels of the NF-kappa B target genes interleukin 8 (IL-8), TNF-alpha and thymic stromal lymphopoietin (TSLP). Likewise, GW501516 prevented the increase in NF-kappa B DNA-binding activity observed in cells exposed to TNF-alpha. The reduction in NF-kappa B activity following GW501516 treatment in cells stimulated with TNF-alpha did not involve either increased I kappa B alpha protein levels or a reduction in the translocation of the p65 subunit of NF-kappa B. In contrast, GW501516 treatment decreased TNF-alpha-induced p65 acetylation. Acetylation of p65 is mainly regulated by p300, a transcriptional co-activator that binds to and acetylates p65. Of note, AMP kinase (AMPK) activation phosphorylates p300 and reduces its binding to p65. GW501516 increased AMPK phosphorylation and the subsequent p300 phosphorylation, leading to a marked reduction in the association between p65 and this transcriptional co-activator. In addition, treatment with the PPAR beta/delta agonist increased SIRT1 protein levels. Finally, the reduction in IL-8 mRNA levels following GW501516 treatment in TNF-alpha-stimulated cells was abolished in the presence of the PPAR beta/delta antagonist GSK0660, the AMPK inhibitor compound C and the SIRT1 inhibitor sirtinol, indicating that the effects of GW501516 on NF-kappa B activity were dependent on PPAR beta/delta, AMPK and SIRT1, respectively. (C) 2010 Elsevier Inc. All rights reserved.
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