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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / deficiency
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Adaptor Proteins, Signal Transducing / immunology
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Biopsy
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Blotting, Western
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Epidermis / drug effects
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Epidermis / immunology
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Epidermis / metabolism
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Epidermis / microbiology
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Immunohistochemistry
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Interleukin-1 / biosynthesis
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Keratinocytes / drug effects
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Keratinocytes / immunology
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Keratinocytes / metabolism*
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Lipopolysaccharides / immunology
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Lipopolysaccharides / pharmacology
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Lipoproteins / metabolism
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Lipoproteins / pharmacology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Myeloid Differentiation Factor 88
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Reverse Transcriptase Polymerase Chain Reaction
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Skin Diseases, Bacterial / immunology
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Skin Diseases, Bacterial / metabolism
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Skin Diseases, Bacterial / microbiology
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Staphylococcal Infections / immunology
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Staphylococcal Infections / metabolism
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Staphylococcus aureus
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Toll-Like Receptor 2 / deficiency
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Toll-Like Receptor 2 / genetics
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Toll-Like Receptor 2 / immunology
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Toll-Like Receptor 2 / metabolism*
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Toll-Like Receptor 4 / deficiency
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / immunology
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Toll-Like Receptor 4 / metabolism
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Tumor Necrosis Factor-alpha / biosynthesis
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beta-Defensins / biosynthesis*
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beta-Defensins / deficiency
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beta-Defensins / genetics
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beta-Defensins / immunology
Substances
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Adaptor Proteins, Signal Transducing
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DEFB103A protein, human
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Interleukin-1
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Lipopolysaccharides
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Lipoproteins
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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RNA, Messenger
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Tlr2 protein, mouse
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Tlr4 protein, mouse
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Toll-Like Receptor 2
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Toll-Like Receptor 4
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Tumor Necrosis Factor-alpha
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beta-Defensins