Rapamycin enhances LPS induction of tissue factor and tumor necrosis factor-α expression in macrophages by reducing IL-10 expression

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 and TF gene expression in macrophages. We determined the role of Akt, the mammalian target of rapamycin (mTOR) and interleukin-10 in the inhibition of LPS-induced proinflammatory cytokine and TF gene expression in peritoneal macrophages (PMs). We used wild type (WT) peritoneal macrophages (PMs), and PMs from PTENflox/flox/LysMCre mice (PTEN−/− PMs), which have increased Akt activity. Pharmacologic inhibition of mTOR with rapamycin inhibited LPS induction of IL-10 mRNA and protein, and enhanced the expression of TF and the proinflammatory cytokine TNFα in WT PMs. Furthermore, neutralizing IL-10 with anti-IL-10 antibody enhanced LPS induction of TNFα and TF expression in WT PMs. The addition of recombinant IL-10 abolished rapamycin enhancement of LPS-induced TNFα and TF expression in WT PMs. Consistent with enhanced Akt activation, LPS-induced IL-10 expression was increased in PTEN−/− PMs compared to WT PMs. In contrast, LPS-induced TNFα and TF expression was significantly reduced in PTEN−/− PMs compared to WT PMs. However, the neutralizing IL-10 antibody did not completely prevent inhibition of LPS-induced TNFα and TF expression in PTEN−/− PMs. The results indicate that mTOR-dependent IL-10 expression leads to inhibition of LPS induction of TF and the proinflammatory cytokine TNFα in WT macrophages. In contrast, the decrease in LPS-induced TNFα and TF expression in PTEN−/− PMs also requires an IL-10-independent pathway.

LPS Induces the Degradation of Programmed Cell Death Protein 4 (PDCD4) to Release Twist2, Activating c-Maf Transcription to Promote Interleukin-10 Production

“…Our findings that PI3K inhibitors and rapamycin reduce LPS induction of IL-10 in macrophages are in agreement with previous studies (19,20). It has previously been demonstrated that rapamycin has the ability to decrease IL-10 mRNA and protein in monocytes and dendritic cells treated with LPS (16, 20 -22).…”

Exogenous Bradykinin Inhibits Tissue Factor Induction and Deep Vein Thrombosis via Activating the eNOS/Phosphoinositide 3-Kinase/Akt Signaling Pathway

“…In addition, there exists a cross-talk between the MAPK and the PI3K pathway on LPSinduced TF expression [41], our in vitro studies indicated that major targets of the PI3K-Akt pathways were the MAPK pathways. Inhibition of the PI3K-Akt pathway was likely to enhance LPS induced activation of the MAPK pathway and the subsequent expression of proinflammatory and procoagulant molecules.…”

“…The discrepancy is mostly probably because LPS induced activation of the PI3K-Akt pathway is slightly delayed relative to activation of the MAPK pathways [41]. Previous data indicated that the p38MAPK, p44/42MAPK, and c-jun terminal NH2-kinase (JNK) signaling pathways downstream NF-kB activation mediated LPS-induced TF expression [26].…”

Ghrelin attenuates intestinal ischemia/reperfusion injury in mice by activating the mTOR signaling pathway

“…Moreover, mTOR negatively regulates the NF-κB pathway (27,49). In monocytes and macrophages, mTOR inhibits NF-κB-dependent pro-inflammatory cytokine IL-12 production and activates STAT3-dependent anti-inflammatory IL-10 production (27,44,45). Previous studies have shown that ghrelin inhibits leptin-induced pro-inflammatory cytokine (IL-1β, TNF-α and IL-6) expression by human T cells and monocytes (20) and suppresses NF-κB activation in human endothelial cells (21).…”