title: Anti-inflammatory actions of acanthoic acid-related diterpenes involve activation of the PI3K p110γ/δ subunits and inhibition of NF-κB.
abstract: The effect of acanthoic acid analogs on the response to proinflammatory challenge was investigated. Some pimarane diterpenes are known activators of the LXRαβ nuclear receptors, but we show here that they also exert a rapid, potent, and selective activation of the p110γ and p110δ subunits of PI3K. Combination of these effects results in an important attenuation of the global transcriptional response to LPS in macrophages. PI3K/Akt activation leads to inhibition of the LPS-dependent stimulation of IKK/NF-κB and p38 and ERK MAPKs. Macrophages from LXRαβ-deficient mice exhibited an inhibition of these pathways similar to the corresponding wild-type cells. Silencing or inhibition of p110γ/δ suppressed the effect of these diterpenes (DTPs) on IKK/NF-κB and MAPKs signaling. Taken together, these data show a multitarget anti-inflammatory mechanism by these DTPs including a selective activation of PI3K isoenzymes.
authors: Instituto de Investigaciones Biomédicas Alberto Sols, Centro Mixto CSIC-UAM, Unidad Asociada Universidad de las Palmas de Gran Canaria, Arturo Duperier 4, 28029 Madrid, Spain.
authors: Paqui G
authors: PG
authors: Través
authors: Instituto de Investigaciones Biomédicas Alberto Sols, Centro Mixto CSIC-UAM, Unidad Asociada Universidad de las Palmas de Gran Canaria, Arturo Duperier 4, 28029 Madrid, Spain.
authors: María
authors: M
authors: Pimentel-Santillana
authors: Structural Biology and BioComputing Programme, National Cancer Research Center (CNIO), Melchor Fernández Almagro 3, 28029 Madrid, Spain.
authors: Daniel
authors: D
authors: Rico
authors: Institut of Microbiology and Hygiene, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
authors: Nuria
authors: N
authors: Rodriguez
authors: Institut of Microbiology and Hygiene, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
authors: Thomas
authors: T
authors: Miethke
authors: Instituto de Investigaciones Biomédicas Alberto Sols, Centro Mixto CSIC-UAM, Unidad Asociada Universidad de las Palmas de Gran Canaria, Arturo Duperier 4, 28029 Madrid, Spain.
authors: Antonio
authors: A
authors: Castrillo
authors: Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0358, USA.
authors: Emmanuel A
authors: EA
authors: Theodorakis
authors: Instituto de Investigaciones Biomédicas Alberto Sols, Centro Mixto CSIC-UAM, Unidad Asociada Universidad de las Palmas de Gran Canaria, Arturo Duperier 4, 28029 Madrid, Spain.
authors: Paloma
authors: P
authors: Martín-Sanz
authors: Sierra Mesa Technologies, 3357 Fortuna Ranch Road, Encinitas, CA 92024, USA. Electronic address: mapdino@aol.com.
authors: Michael A
authors: MA
authors: Palladino
authors: Instituto de Investigaciones Biomédicas Alberto Sols, Centro Mixto CSIC-UAM, Unidad Asociada Universidad de las Palmas de Gran Canaria, Arturo Duperier 4, 28029 Madrid, Spain. Electronic address: lbosca@iib.uam.es.
authors: Lisardo
authors: L
authors: Boscá
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000737:chemistry* / Q000378:metabolism*; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008968:Molecular Conformation; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D041681:NIH 3T3 Cells; D057093:Orphan Nuclear Receptors / Q000172:deficiency / Q000378:metabolism; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004224:Diterpenes; D008070:Lipopolysaccharides; D000071518:Liver X Receptors; D016328:NF-kappa B; D057093:Orphan Nuclear Receptors; D021122:Protein Subunits; C099958:acanthoic acid; D058543:Class Ia Phosphatidylinositol 3-Kinase