MTOR‐dependent IL‐10 expression inhibits LPS induction of tissue factor and cytokines in macrophages.

Abstract

Bacterial lipopolysaccharide (LPS) induces monocytes/macrophages to express proinflammatory cytokines and tissue factor (TF), the primary activator of the coagulation cascade. Anti‐inflammatory signaling pathways including the phosphatidylinositol‐3‐kinase (PI3K)‐Akt pathway inhibit proinflammatory gene expression in macrophages. We determined whether the mammalian target of rapamycin (mTOR) and induction of the anti‐inflammatory cytokine interleukin‐10 (IL‐10) inhibited LPS‐induced proinflammatory and TF gene expression in peritoneal macrophages (PMs) in a PI3K‐Akt‐dependent manner. We used wild type (WT) peritoneal macrophages (PMs), and PMs from PTENflox/flox/LysMCre mice (PTEN−/− PMs), which have increased Akt activity. LPS induction of IL‐10 mRNA and protein was increased in PTEN−/− PMs compared to WT PMs. Pharmacologic inhibition of mTOR with rapamycin inhibited LPS induction of IL‐10 mRNA and protein, and enhanced the expression of TF and the proinflammatory cytokines interleukin‐6 (IL‐6) and tumor necrosis factor‐α (TNFα). Neutralization of endogenous IL‐10 also enhanced LPS induction of TNFα, IL‐6 and TF expression in WT and PTEN−/− PMs. The results indicate that mTOR‐dependent IL‐10 expression leads to inhibition of LPS induction of TF and the proinflammatory cytokines IL‐6 and TNFα in WT macrophages