| First Author | Baker AK | Year | 2009 |
| Journal | Mol Immunol | Volume | 46 |
| Issue | 11-12 | Pages | 2249-55 |
| PubMed ID | 19447494 | Mgi Jnum | J:149453 |
| Mgi Id | MGI:3848559 | Doi | 10.1016/j.molimm.2009.04.011 |
| Citation | Baker AK, et al. (2009) Rapamycin enhances LPS induction of tissue factor and tumor necrosis factor-alpha expression in macrophages by reducing IL-10 expression. Mol Immunol 46(11-12):2249-55 |
| abstractText | 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. |
