Antimicrobial peptides human beta-defensins stimulate epidermal keratinocyte migration, proliferation and production of proinflammatory cytokines and chemokines.
Besides their microbicidal functions, human beta-defensins (hBD) and LL-37 activate different immune and inflammatory cells, and their expression is enhanced in inflamed skin and cutaneous wound sites. To protect against pathogens, the skin produces antimicrobial peptides including hBDs and LL-37. Therefore, the aim of our study was to investigate whether hBDs participate in cutaneous inflammation and wound healing by inducing keratinocyte migration, proliferation, and production of proinflammatory cytokines/chemokines. We found that hBD-2, -3, and -4 but not hBD-1 stimulated human keratinocytes to increase their gene expression and protein production of IL-6, IL-10, IP-10, monocyte chemoattractant protein-1, macrophage inflammatory protein-3alpha, and RANTES. This stimulatory effect was markedly suppressed by pertussis toxin and U-73122, inhibitors for G protein and phospholipase C, respectively. We also demonstrated that hBDs elicited intracellular Ca2+ mobilization, and increased keratinocyte migration, and proliferation. In addition, these peptides induced phosphorylation of EGFR, signal transducer and activator of transcription (STAT)1, and STAT3, which are intracellular signaling molecules involved in keratinocyte migration and proliferation. In our study, inhibition of these molecules significantly reduced hBD-mediated keratinocyte migration and proliferation. In conclusion, this study provides evidence that human antimicrobial peptides may be involved in skin immunity through stimulating cytokine/chemokine production, and participate in wound healing by promoting keratinocyte migration and proliferation.
Niyonsaba
François
F
Atopy (Allergy) Research Center, Juntendo University School of Medicine, Tokyo, Japan. francois@med.juntendo.ac.jp
Ushio
Hiroko
H
Nakano
Nobuhiro
N
Ng
William
W
Sayama
Koji
K
Hashimoto
Koji
K
Nagaoka
Isao
I
Okumura
Ko
K
Ogawa
Hideoki
H
D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000502:physiology*; D002465:Cell Movement; D049109:Cell Proliferation; D054418:Chemokine CCL20; D018946:Chemokine CCL5 / Q000378:metabolism; D018925:Chemokines / Q000096:biosynthesis*; D019742:Chemokines, CC / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis*; D000078404:Epidermal Cells; D004963:Estrenes / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology; D015398:Signal Transduction; D023083:beta-Defensins / Q000378:metabolism / Q000502:physiology*
D023181:Antimicrobial Cationic Peptides; C108355:CCL20 protein, human; D054418:Chemokine CCL20; D018946:Chemokine CCL5; D018925:Chemokines; D019742:Chemokines, CC; D016207:Cytokines; D004963:Estrenes; D019402:Macrophage Inflammatory Proteins; D011760:Pyrrolidinones; D023083:beta-Defensins; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione