Anti-inflammatory Actions of Acanthoic Acid-Related Diterpenes Involve Activation of the PI3K p110 gamma/delta Subunits and Inhibition of NF-kappa B

作者：Traves Paqui G; Pimentel Santillana Maria; Rico Daniel; Rodriguez Nuria; Miethke Thomas; Castrillo Antonio; Theodorakis Emmanuel A; Martin Sanz Paloma; Palladino Michael A^*; Bosca Lisardo

来源：Chemistry & Biology, 2014, 21(8): 955-966.

DOI：10.1016/j.chembiol.2014.06.005

The effect of acanthoic acid analogs on the response to proinflammatory challenge was investigated. Some pimarane diterpenes are known activators of the LXR alpha beta nuclear receptors, but we show here that they also exert a rapid, potent, and selective activation of the p110 gamma and p110 gamma 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-kappa B and p38 and ERK MAPKs. Macrophages from LXR alpha beta-deficient mice exhibited an inhibition of these pathways similar to the corresponding wild-type cells. Silencing or inhibition of p110 gamma/delta suppressed the effect of these diterpenes (DTPs) on IKK/NF-kappa B and MAPKs signaling. Taken together, these data show a multitarget anti-inflammatory mechanism by these DTPs including a selective activation of PI3K isoenzymes.

• 出版日期2014-8-14