Anti-inflammatory actions of acanthoic acid-related diterpenes involve activation of the PI3K p110γ/δ subunits and inhibition of NF-κB

et al.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.This work was supported by grants BFU2011/24760 and RD12/0042/0019 from MINECO and RIC (ISCIII), Spain, and S2010/BMD2378 from Comunidad de Madrid to L.B.; SAF2011-29244 and S2010/BMD2350 to A.C.; and NIH grant R44AI49014 awarded to M.A.P.Peer Reviewe

Anti-inflammatory Actions of Acanthoic Acid-Related Diterpenes Involve Activation of the PI3K p110γ/δ Subunits and Inhibition of NF-κB

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. Diterpenes exert anti-inflammatory effects broadly impacting the NF-κB pathway, and Través etal. now show selective activation of the p110γ/δ PI3K isoforms in macrophages by a class of acanthoic-acid related molecules. © 2014 Elsevier Ltd