title: Induction of beta-defensin 3 in keratinocytes stimulated by bacterial lipopeptides through toll-like receptor 2.
abstract: The epidermis, which covers the surface of all mammals, serves as a front line of defense against the invasion of pathogenic microbes and acts as a crucial site for innate immune responses. Various antimicrobial molecules are expressed not only on the surfaces of monocytes but also on epithelial cells. beta-Defensins, a family of antimicrobial peptides, are produced by several types of epithelial cells, including keratinocytes. However, the induction pathways for beta-defensins in keratinocytes are not fully understood. We hypothesized that bacterial components would trigger the expression of beta-defensins in keratinocytes through a toll-like receptor (TLR)-MyD88 signaling pathway that plays important roles in innate immunity. Production of TNF-alpha and IL-1 alpha following stimulation with lipopolysaccharide or bacterial lipopeptides was completely abolished in TLR2&TLR4-doubly deficient keratinocytes and in MyD88-deficient keratinocytes. Expression of murine beta-defensin was upregulated by bacterial lipopeptides in wild-type keratinocytes, while it was attenuated in TLR2-deficient keratinocytes. To evaluate the in vivo role of TLRs in keratinocytes, we inoculated Staphylococcus aureus into the tail skin from TLR2-deficient mice that had been grafted on the dorsal skin of syngeneic mice. The grafted skin from TLR2-deficient mice resulted in erosion. These studies strongly suggest that the TLR2-MyD88-dependent pathway in keratinocytes is essential for antimicrobial activity in vivo.
authors.affiliation: Department of Dermatology, Course of Molecular Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Sumikawa
authors.forename: Hideo
authors.initials: H
authors.lastname: Asada
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Hoshino
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Azukizawa
authors.forename: Ichiro
authors.initials: I
authors.lastname: Katayama
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Satoshi
authors.initials: S
authors.lastname: Itami
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000276:immunology / Q000378:metabolism; D000818:Animals; D001706:Biopsy; D015153:Blotting, Western; D004817:Epidermis / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000096:biosynthesis; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008074:Lipoproteins / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017192:Skin Diseases, Bacterial / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D013203:Staphylococcal Infections / Q000276:immunology / Q000378:metabolism; D013211:Staphylococcus aureus; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D023083:beta-Defensins / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C422950:DEFB103A protein, human; D007375:Interleukin-1; D008070:Lipopolysaccharides; D008074:Lipoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D023083:beta-Defensins