PECAM-1 ligation negatively regulates TLR4 signaling in macrophages.
Uncontrolled TLR4 signaling may induce excessive production of proinflammatory cytokines and lead to harmful inflammation; therefore, negative regulation of TLR4 signaling attracts much attention now. PECAM-1, a member of Ig-ITIM family, can mediate inhibitory signals in T cells and B cells. However, the role and the mechanisms of PECAM-1 in the regulation of TLR4-mediated LPS response in macrophages remain unclear. In this study, we demonstrate that PECAM-1 ligation with CD38-Fc fusion protein negatively regulates LPS-induced proinflammatory cytokine TNF-alpha, IL-6, and IFN-beta production by inhibiting JNK, NF-kappaB, and IFN regulatory factor 3 activation in macrophages. In addition, PECAM-1 ligation-recruited Src homology region 2 domain-containing phosphatase 1 (SHP-1) and Src homology region 2 domain-containing phosphatase 2 (SHP-2) may be involved in the inhibitory effect of PECAM-1 on TLR4 signaling. Consistently, silencing of PECAM-1 enhances the macrophage response to LPS stimulation. Taken together with the data that PECAM-1 is constitutively expressed in macrophages and its expression is up-regulated by LPS stimulation, PECAM-1 might function as a feedback negative regulator of LPS inflammatory response in macrophages. This study may provide a potential target for intervention of inflammatory diseases.
Rui
Yuxiang
Y
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
Liu
Xingguang
X
Li
Nan
N
Jiang
Yingming
Y
Chen
Guoyou
G
Cao
Xuetao
X
Wang
Jianli
J
D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics; D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology*; D020869:Gene Expression Profiling; D006801:Humans; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000276:immunology; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D007700:Kinetics; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000502:physiology*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000276:immunology; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000187:drug effects / Q000378:metabolism*
D016207:Cytokines; D020672:I-kappa B Proteins; D050838:Interferon Regulatory Factor-3; D008070:Lipopolysaccharides; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000072000:NF-KappaB Inhibitor alpha; D048031:JNK Mitogen-Activated Protein Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse; D051997:ADP-ribosyl Cyclase 1