Human beta-defensin-2 functions as a chemotactic agent for tumour necrosis factor-alpha-treated human neutrophils.
Neutrophils are the effector cells in both innate and adaptive immunity, where they perform the functions of phagocytosis and killing of bacteria. They respond to a large number of chemoattractants, but their response to epithelial cell-derived human beta-defensins (hBD) has not been investigated. Here we report that hBD-2, but not hBD-1, is a specific chemoattractant for tumour necrosis factor (TNF)-alpha-treated human neutrophils. The optimal concentration required for maximal chemotactic activity was 5 micro g/ml. The effect of hBD-2 on neutrophils was dependent on the G-protein-phospholipase C pathway, as demonstrated by inhibition by pertussis toxin and U-73122. In addition, ligand-receptor analysis indicated that the binding of hBD-2 was markedly inhibited by macrophage inflammatory protein (MIP)-3alpha, a specific and unique ligand for CCR6. Furthermore, anti-CCR6 antibody could almost completely suppress the cell migration induced by hBD-2, suggesting that hBD-2 mainly utilizes CCR6 as a functional receptor. Thus, our finding that hBD-2 is a potent chemoattractant for human neutrophils through specific receptors provides a novel mechanism by which this peptide contributes to the host defence system by recruiting neutrophils to inflammation/infection sites. This also suggests an important link between epithelial cell-derived antibacterial peptides and neutrophils during infection or inflammation.
Department of Host Defense and Biochemical Research, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
François
F
Niyonsaba
Hideoki
H
Ogawa
Isao
I
Nagaoka
D000890:Anti-Infective Agents / Q000276:immunology; D002614:Chelating Agents; D054418:Chemokine CCL20; D019742:Chemokines, CC / Q000276:immunology; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000276:immunology; D004963:Estrenes / Q000276:immunology; D006801:Humans; D016209:Interleukin-8 / Q000276:immunology*; D019402:Macrophage Inflammatory Proteins / Q000276:immunology; D018375:Neutrophil Activation / Q000276:immunology; D009504:Neutrophils / Q000276:immunology*; D037342:Pertussis Toxin / Q000276:immunology; D011760:Pyrrolidinones / Q000276:immunology; D054399:Receptors, CCR6; D019707:Receptors, Chemokine / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D023083:beta-Defensins / Q000276:immunology*
D000890:Anti-Infective Agents; C108355:CCL20 protein, human; C106311:CCR6 protein, human; D002614:Chelating Agents; D054418:Chemokine CCL20; D019742:Chemokines, CC; C406407:DEFB1 protein, human; C106641:DEFB4A protein, human; D004963:Estrenes; D016209:Interleukin-8; D019402:Macrophage Inflammatory Proteins; D011760:Pyrrolidinones; D054399:Receptors, CCR6; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; D023083:beta-Defensins; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D037342:Pertussis Toxin