Journal
CELLULAR SIGNALLING
Volume 20, Issue 12, Pages 2266-2275Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2008.08.022
Keywords
CPG; Toll-like receptor; Foam cell; ROS; Nox; Lox-1
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Funding
- Korean Science and Engineering Foundation [R01-2007-000-20087-0]
- Yeungnam University [R13-2005-005-02001-0]
- National Research Foundation of Korea [R01-2007-000-20087-0] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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The formation of foam cells is the hallmark of early atherosclerotic lesions, and the uptake of modified low-density lipoprotein (LDL) by macrophage scavenger receptors is thought to be a key process in their formation. In this study, we examined the role of lectin-like oxLDL receptor-1 (Lox-1) and NADPH oxidase 1 (Nox1) in toll-like receptor 9 (TLR9)-mediated foam cell formation. TLR9 activation of Raw264.7 cells or mouse primary peritoneal macrophages by CpG ODN treatment enhanced Lox-1 gene and protein expression. In addition, CpG ODN-induced Nox1 mRNA expression, which in turn increased foam cell formation. The inhibition of CpG ODN-induced reactive oxygen species (ROS) generation by treatment with antioxidants, as well as with knockdown of Nox1 using siRNA, suppressed the formation of foam cells. The induction of Lox-1 and Nox1 by CpG ODN was regulated via the TLR9-p38 MAPK signaling pathway. CpG ODN also increased NF kappa B activity, and a potent inhibitor of NF kappa B that significantly blocked CpG-induced Nox1 expression, suggesting that Nox1 regulation is mediated through an NF kappa B-dependent mechanism. Taken together, these results suggest that a combination of Lox-1 and Nox1 plays a key role in the TLR9-mediated formation of foam cells via the p38 MAPK pathway. (c) 2008 Elsevier Inc. All rights reserved.
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