Journal
MOLECULAR IMMUNOLOGY
Volume 46, Issue 11-12, Pages 2249-2255Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.molimm.2009.04.011
Keywords
Tissue factor; Lipopolysaccharide; Interleukin-10; Akt; Mammalian target of rapamycin
Categories
Funding
- National Center for Research Resources (NCRR) [P20 RR016475]
- NIH [P20 RR021940]
Ask authors/readers for more resources
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 TNF alpha in WT PMs. Furthermore, neutralizing IL-10 with anti-IL-10 antibody enhanced LPS induction of TNF alpha and TF expression in WT PMs. The addition of recombinant IL-10 abolished rapamycin enhancement of LPS-induced TNF alpha 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 TNF alpha 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 TNF alpha 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 TNF alpha in WT macrophages. In contrast, the decrease in LPS-induced TNF alpha and TF expression in PTEN-/- PMs also requires an IL-10-independent pathway. (C) 2009 Elsevier Ltd. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available