期刊
CELL ADHESION & MIGRATION
卷 1, 期 3, 页码 115-123出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/cam.1.3.4984
关键词
P-selectin (CD62P); P-selectin glycoprotein ligand-1 (PSGL-1); integrins; G protein-coupled receptor (GPCR); human neutrophils; cell adhesion
类别
资金
- National Science Foundation of China [30421005, 30623003, 30400245, 30630036]
- Ministry of Science and Technology of China [2002CB513006, 2006CB943902, 2006AA02Z169, 2007CB947100, 2007CB914501]
- Chinese Academy of Sciences [KSCX2-YW-R-67, KJCX2-YW-H08]
- Shanghai Municipal Commission for Science and Technology [04JC14078, 06DZ22032, 055407035, 058014578]
- National Institute of Health [RO1AI064743]
Endothelial and platelet P-selectin (CD62P) and leukocyte integrin alpha(M)beta(2) (CD11bCD18, Mac-1) are cell adhesion molecules essential for host defense and innate immunity. Upon inflammatory challenges, P-selectin binds to PSGL-1 (P-selectin glycoprotein ligand-1, CD162) to mediate neutrophil rolling, during which integrins become activated by extracellular stimuli for their firm adhesion in a G-protein coupled receptor (GPCR)-dependent mechanism. Here we show that cross-linking of PSGL-1 by dimeric or multimeric forms of platelet P-selectin, P-selectin receptor-globulin, anti-PSGL-1 mAb and its F(ab')(2) induced adhesion of human neutrophils to fibrinogen (Fg) and intercellular cell adhesion molecule-1 (ICAM-1, CD54) and triggered a moderate clustering of alpha(M)beta(2), but monomeric forms of soluble P-selectin and anti-PSGL-1 Fab did not. Interestingly, P-selectin did not induce a detectable interleukine-8 (IL-8) secretion (<0.1 ng/ml) in 30 minutes, whereas a high concentration of IL-8 (>50 ng/ml) was required to increase neutrophil adhesion to Fg. P-selectin-induced neutrophil adhesion was significantly inhibited by PP2 (a Src kinase inhibitor), but not by pertussis toxin (PTX; a GPCR inhibitor). Activated platelets also increased neutrophil binding to fibrinogen and triggered tyrosine phosphorylation of cellular proteins. Our results indicate that P-selectin-induced integrin activation (Src kinase-dependent) is distinct from that elicited by cytokines, chemokines, chemoattractants (GPCR-dependent), suggesting that these two signal transduction pathways may cooperate for maximal activation of leukocyte integrins.
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