Epithelial cell-derived human beta-defensin-2 acts as a chemotaxin for mast cells through a pertussis toxin-sensitive and phospholipase C-dependent pathway.
Mast cells are known to accumulate at the sites of inflammation in response to chemoattractants generated in the local milieu. Since human beta-defensin-2 (hBD-2) is generated in several epithelial tissues where mast cells are present and because we have recently reported that this human antibacterial peptide induces mast cell degranulation, we thus hypothesized that hBD-2 could be a mast cell chemotaxin. Here we report that hBD-2 directly and specifically induces mast cell migration with an optimal concentration of 3 microg/ml. Checkerboard analysis showed that the migration was more chemotactic rather than chemokinetic. Moreover, Scatchard analysis using 125I-labeled hBD-2 revealed that mast cells have at least two classes of receptors, high- and low-affinity receptors, for this peptide. Moreover, the competitive binding assay suggested that hBD-2 is unlikely to utilize CCR6, a functional receptor for hBD-2-mediated dendritic and T cell migration, on mast cells. In addition, treatment of mast cells with G protein inhibitor, pertussis toxin, and phospholipase C inhibitor, U-73122, abolished the cell chemotaxis in response to hBD-2, indicating that the G protein-phospholipase C signaling pathway is involved in hBD-2-induced mast cell activation. Thus, we suggest that hBD-2, which was originally believed to be involved in innate host defense, may participate in the recruitment of mast cells to inflammation foci.
Niyonsaba
François
F
Department of Biochemistry, School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Iwabuchi
Kazuhisa
K
Matsuda
Hiroshi
H
Ogawa
Hideoki
H
Nagaoka
Isao
I
D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002630:Chemotactic Factors / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D004848:Epithelium / Q000378:metabolism*; D004963:Estrenes / Q000037:antagonists & inhibitors; D006801:Humans; D008407:Mast Cells / Q000187:drug effects*; D037342:Pertussis Toxin; D011760:Pyrrolidinones / Q000037:antagonists & inhibitors; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D010738:Type C Phospholipases / Q000378:metabolism*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D023083:beta-Defensins / Q000494:pharmacology / Q000502:physiology*
D002630:Chemotactic Factors; C106641:DEFB4A protein, human; D004963:Estrenes; D011760:Pyrrolidinones; D010566:Virulence Factors, Bordetella; D023083:beta-Defensins; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D037342:Pertussis Toxin; D010738:Type C Phospholipases