Gene interactions and pathways from curated databases and text-mining
Mol Immunol 2009, PMID: 19447494

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

Baker, Alyson K; Wang, Ruipeng; Mackman, Nigel; Luyendyk, James P

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 PTEN(flox/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 TNFalpha in WT PMs. Furthermore, neutralizing IL-10 with anti-IL-10 antibody enhanced LPS induction of TNFalpha and TF expression in WT PMs. The addition of recombinant IL-10 abolished rapamycin enhancement of LPS-induced TNFalpha 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 TNFalpha 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 TNFalpha 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 TNFalpha in WT macrophages. In contrast, the decrease in LPS-induced TNFalpha and TF expression in PTEN(-/-) PMs also requires an IL-10-independent pathway.

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Text Mining Data

TNFalpha ⊣ mTOR: " 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 TNFalpha in WT PMs "

TNFalpha → IL-10: " Furthermore, neutralizing IL-10 with anti-IL-10 antibody enhanced LPS induction of TNFalpha and TF expression in WT PMs "

TNFalpha → LPS: " Furthermore, neutralizing IL-10 with anti-IL-10 antibody enhanced LPS induction of TNFalpha and TF expression in WT PMs "

LPS → IL-10: " Furthermore, neutralizing IL-10 with anti-IL-10 antibody enhanced LPS induction of TNFalpha and TF expression in WT PMs "

TNFalpha → LPS: " The addition of recombinant IL-10 abolished rapamycin enhancement of LPS induced TNFalpha 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 "

IL-10 → LPS: " The addition of recombinant IL-10 abolished rapamycin enhancement of LPS induced TNFalpha 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 "

TNFalpha → LPS: " In contrast, LPS induced TNFalpha and TF expression was significantly reduced in PTEN ( -/- ) PMs compared to WT PMs "

TNFalpha → LPS: " However, the neutralizing IL-10 antibody did not completely prevent inhibition of LPS induced TNFalpha and TF expression in PTEN ( -/- ) PMs "

TNFalpha ⊣ IL-10: " The results indicate that mTOR dependent IL-10 expression leads to inhibition of LPS induction of TF and the proinflammatory cytokine TNFalpha in WT macrophages "

LPS ⊣ IL-10: " The results indicate that mTOR dependent IL-10 expression leads to inhibition of LPS induction of TF and the proinflammatory cytokine TNFalpha in WT macrophages "

IL-10 — mTOR: " The results indicate that mTOR dependent IL-10 expression leads to inhibition of LPS induction of TF and the proinflammatory cytokine TNFalpha in WT macrophages "

TNFalpha → LPS: " In contrast, the decrease in LPS induced TNFalpha and TF expression in PTEN ( -/- ) PMs also requires an IL-10 independent pathway "

Manually curated Databases

No curated data.