期刊
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
卷 411, 期 3, 页码 516-522出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2011.06.161
关键词
SR-A; Macrophages; LPS; TLR4; Septic shock
资金
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [B20390113, 21790388]
- Graduate School of Medical Sciences, Kumamoto University, MEXT, Japan
- Grants-in-Aid for Scientific Research [23790747, 23659204, 21790388] Funding Source: KAKEN
The class A scavenger receptor (SR-A. CD204), one of the principal receptors expressed on macrophages, has been found to regulate inflammatory response and attenuate septic endotoxemia. However, the detailed mechanism of this process has not yet been well characterized. To clarify the regulative mechanisms of lipopolysaccharide (LPS)-induced macrophage activation by SR-A, we evaluated the activation of Toll-like receptor 4 (TLR4)-mediated signaling molecules in SR-A-deficient (SR-A(-/-)) macrophages. In a septic shock model, the blood levels of tumor necrosis factor (TNE)-alpha, interleukin (IL)-6 and interferon (IFN)-beta were significantly increased in SR-A(-/-) mice compared to wild-type mice, and elevated nuclear factor kappa B (NF kappa B) activation was detected in SR-A(-/-) macrophages. SR-A deletion increased the production of pro-inflammatory cytokines, and the phosphorylation of mitogen-activated protein kinase (MAPK) and NF kappa B in vitro. SR-A deletion also promoted the nuclear translocation of NF kappa B and IFN regulatory factor (IRF)-3. In addition, a competitive binding assay with acetylated low-density lipoprotein, an SR-A-specific ligand, and anti-SR-A antibody induced significant activation of TLR4-mediated signaling molecules in wild-type macrophages but not in SR-A(-/-) macrophages. These results suggest that SR-A suppresses the macrophage activation by inhibiting the binding of LPS to TLR4 in a competitive manner and it plays a pivotal role in the regulation of the LPS-induced inflammatory response. (C) 2011 Elsevier Inc. All rights reserved.
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