期刊
JOURNAL OF LEUKOCYTE BIOLOGY
卷 88, 期 4, 页码 609-618出版社
WILEY
DOI: 10.1189/jlb.0809588
关键词
Toll-like receptors; complement; inflammation
资金
- National Institutes of Health [P50-GM-53789, R01-HL-079669]
- VA Merit Award
- American College of Surgeons
TLRs and complement are critical to the host response in sepsis, trauma, and ischemia/reperfusion. We hypothesize that TLR stimulation leads to synthesis and release of complement components by macrophages, an important source of extrahepatic complement. RAW264.7 macrophages or peritoneal macrophages from WT and TLR4-, TLR3-, TRIF-, or MyD88-deficient mice were cultured under standard conditions. In some experiments, cells were pretreated with inhibitors of MAPKs or a NF-kappa B inhibitor. Cells were stimulated with TLR ligands at known stimulatory concentrations. Intratracheal and i.p. injections were also performed in mice. RT-PCR, Western blotting, and immunocytochemistry were used for analysis. Using a RT-PCR-based panel, we demonstrate that of 18 complement components tested, factor B of the alternative pathway is the most robustly up-regulated complement component in macrophages in response to LPS. This up-regulation results in release of factor B into the media. Upregulation of factor B by LPS is dependent on TLR4, TRIF, JNK, and NF-kappa B. A screen of other TLR ligands demonstrated that stimulation with poly I: C (dsRNA analog) also results in up-regulation of factor B, which is dependent on JNK and NF-kappa B but independent of TLR3 and TRIF. Up-regulation of factor B is also observed after intratracheal and i.p. injection of LPS or poly I: C in vivo. PRR stimulation profoundly influences production and release of factor B by macrophages. Understanding the mechanisms of PRR-mediated complement production may lead to strategies aimed at preventing tissue damage in diverse settings, including sepsis, trauma, and ischemia/reperfusion. J. Leukoc. Biol. 88: 609-618; 2010.
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