Genetic and pharmacologic alteration of PI3K/Akt activity modulates LPS‐induced cytokine expression in vitro and in vivo .

Abstract

Pharmacologic inhibition of phosphatidylinositol–3-kinase (PI3K) enhances LPS-induction of IL-6 gene expression in monocytes and inflammation in endotoxemic mice. Class IA PI3K is comprised of a 110kD catalytic subunit (α, β, or δ) and a 85kD regulatory subunit (p85α or p85β). PI3K activation of Akt is counterbalanced by the phosphatase PTEN. Loss of p85α (p85α−/−) results in reduced PI3K/Akt activity, whereas loss of PTEN (PTEN−/−) enhances Akt activity. In vitro, peritoneal macrophages (PMs) from p85α−/− mice produced significantly more IL-6 upon LPS stimulation compared to wild-type PMs, whereas LPS-induced IL-6 expression was reduced in PMs from PTEN−/− mice. In vivo, transplantation of bone marrow from p85α−/− mice into C57Bl/6 recipient mice increased plasma IL-6 concentration and reduced survival after LPS treatment compared to mice receiving bone marrow from wild-type mice. Next, we tested the hypothesis that insulin attenuates inflammation in endotoxemic mice, in part, by activation of PI3K. The PI3K inhibitor wortmannin reduced the protective effect of insulin in endotoxemic mice. In summary, our data support the hypothesis that PI3K activity in the monocyte/macrophage suppresses inflammation in endotoxemia. Furthermore, the data suggest that the anti-inflammatory action of insulin may be dependent on its ability to activate PI3K signaling pathways.