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The peroxisome proliferator-activated receptor β/δ (PPARβ/δ) agonist GW501516 prevents TNF-α-induced NF-κB activation in human HaCaT cells by reducing p65 acetylation through AMPK and SIRT1.
Biochem Pharmacol. 2011 Feb 15; 81(4):534-43.BP

Abstract

Nuclear factor (NF)-κB 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) β/δ prevented TNF-α-induced NF-κB activation in human HaCaT keratinocytes and, if so, to determine the mechanism involved. The PPARβ/δ agonist GW501516 inhibited the increase caused by TNF-α in the mRNA levels of the NF-κB target genes interleukin 8 (IL-8), TNF-α and thymic stromal lymphopoietin (TSLP). Likewise, GW501516 prevented the increase in NF-κB DNA-binding activity observed in cells exposed to TNF-α. The reduction in NF-κB activity following GW501516 treatment in cells stimulated with TNF-α did not involve either increased IκBα protein levels or a reduction in the translocation of the p65 subunit of NF-κB. In contrast, GW501516 treatment decreased TNF-α-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 PPARβ/δ agonist increased SIRT1 protein levels. Finally, the reduction in IL-8 mRNA levels following GW501516 treatment in TNF-α-stimulated cells was abolished in the presence of the PPARβ/δ antagonist GSK0660, the AMPK inhibitor compound C and the SIRT1 inhibitor sirtinol, indicating that the effects of GW501516 on NF-κB activity were dependent on PPARβ/δ, AMPK and SIRT1, respectively.

Authors+Show Affiliations

Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, Institut de Biomedicina de la UB (IBUB), Spain.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21146504

Citation

Barroso, Emma, et al. "The Peroxisome Proliferator-activated Receptor Β/δ (PPARβ/δ) Agonist GW501516 Prevents TNF-α-induced NF-κB Activation in Human HaCaT Cells By Reducing P65 Acetylation Through AMPK and SIRT1." Biochemical Pharmacology, vol. 81, no. 4, 2011, pp. 534-43.
Barroso E, Eyre E, Palomer X, et al. The peroxisome proliferator-activated receptor β/δ (PPARβ/δ) agonist GW501516 prevents TNF-α-induced NF-κB activation in human HaCaT cells by reducing p65 acetylation through AMPK and SIRT1. Biochem Pharmacol. 2011;81(4):534-43.
Barroso, E., Eyre, E., Palomer, X., & Vázquez-Carrera, M. (2011). The peroxisome proliferator-activated receptor β/δ (PPARβ/δ) agonist GW501516 prevents TNF-α-induced NF-κB activation in human HaCaT cells by reducing p65 acetylation through AMPK and SIRT1. Biochemical Pharmacology, 81(4), 534-43. https://doi.org/10.1016/j.bcp.2010.12.004
Barroso E, et al. The Peroxisome Proliferator-activated Receptor Β/δ (PPARβ/δ) Agonist GW501516 Prevents TNF-α-induced NF-κB Activation in Human HaCaT Cells By Reducing P65 Acetylation Through AMPK and SIRT1. Biochem Pharmacol. 2011 Feb 15;81(4):534-43. PubMed PMID: 21146504.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The peroxisome proliferator-activated receptor β/δ (PPARβ/δ) agonist GW501516 prevents TNF-α-induced NF-κB activation in human HaCaT cells by reducing p65 acetylation through AMPK and SIRT1. AU - Barroso,Emma, AU - Eyre,Elena, AU - Palomer,Xavier, AU - Vázquez-Carrera,Manuel, Y1 - 2010/12/10/ PY - 2010/10/15/received PY - 2010/11/30/revised PY - 2010/12/01/accepted PY - 2010/12/15/entrez PY - 2010/12/15/pubmed PY - 2011/2/24/medline SP - 534 EP - 43 JF - Biochemical pharmacology JO - Biochem Pharmacol VL - 81 IS - 4 N2 - Nuclear factor (NF)-κB 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) β/δ prevented TNF-α-induced NF-κB activation in human HaCaT keratinocytes and, if so, to determine the mechanism involved. The PPARβ/δ agonist GW501516 inhibited the increase caused by TNF-α in the mRNA levels of the NF-κB target genes interleukin 8 (IL-8), TNF-α and thymic stromal lymphopoietin (TSLP). Likewise, GW501516 prevented the increase in NF-κB DNA-binding activity observed in cells exposed to TNF-α. The reduction in NF-κB activity following GW501516 treatment in cells stimulated with TNF-α did not involve either increased IκBα protein levels or a reduction in the translocation of the p65 subunit of NF-κB. In contrast, GW501516 treatment decreased TNF-α-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 PPARβ/δ agonist increased SIRT1 protein levels. Finally, the reduction in IL-8 mRNA levels following GW501516 treatment in TNF-α-stimulated cells was abolished in the presence of the PPARβ/δ antagonist GSK0660, the AMPK inhibitor compound C and the SIRT1 inhibitor sirtinol, indicating that the effects of GW501516 on NF-κB activity were dependent on PPARβ/δ, AMPK and SIRT1, respectively. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/21146504/The_peroxisome_proliferator_activated_receptor_β/δ__PPARβ/δ__agonist_GW501516_prevents_TNF_α_induced_NF_κB_activation_in_human_HaCaT_cells_by_reducing_p65_acetylation_through_AMPK_and_SIRT1_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(10)00845-2 DB - PRIME DP - Unbound Medicine ER -