2005 Fiscal Year Final Research Report Summary
Regulation of skin innate immunity by epidermal differentiation
| Project/Area Number |
15209035
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Dermatology
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| Research Institution | Ehime University |
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Principal Investigator |
HASHIMOTO Koji EHIME UNIVERSITY, SCHOOL OF MEDICINE, PROFESSOR, 医学部, 教授 (00110784)
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| Co-Investigator(Kenkyū-buntansha) |
SAYAMA Koji EHIME UNIVERSITY, SCHOOL OF MEDICINE, ASSOCIATE PROFESSOR, 医学部, 助教授 (80187286)
SHIRAKATA Yuji EHIME UNIVERSITY, SCHOOL OF MEDICINE, INSTRUCTOR, 医学部, 講師 (50226320)
ICHIJO Hidenori THE UNIVERSITY OF TOKYO, GRADUATE SCHOOL OF PHARMACEUTICAL SCIENCES, PROFESSOR, 大学院・薬学系研究科, 教授 (00242206)
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| Project Period (FY) |
2003 – 2005
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| Keywords | Epidermis / Keratinocyte / Differentiation / Innate Immunity / Toll-like receptor / Anti-microbial peptide / Wound Healing / Virus infection |
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| Research Abstract |
Epidermal keratinocytes differentiate and form a multilayered epidermis, which is the primary barrier between the body and the outer environment. As the epidermis is constantly exposed to a variety of microbial pathogens, its function of resisting microbial pathogens is vital.
Poly (I:C) treatment induced MIP-1? production in normal human keratinocytes. A neutralizing antibody for IFN-? significantly inhibited the poly (I:C)-induced MIP-1? production indicating that MIP-1??production is via IFN-?. IFN-? priming enhanced TLR3 expression and MIP-1? production in poly (I:C)-treated keratinocytes. This suggests that IFN-? enhanced the TLR3 expression and reinforced the response of keratinocytes to poly (I:C), which resulted in an increase in MIP-1??production. Therfore, normal human keratinocytes produce MIP-1? in response to dsRNA via TLR3, and this production is regulated by IFN-? ??.
Immunohistochemical analysis revealed that the upper epidermis of normal human skin expresses ?-defensins (hBD) 1-3 and LL37. Transfection of ASK1-ΔN significantly enhanced the expression of hBD 1-3 and LL37 in normal human keratinocytes. In addition, a p38 inhibitor abolished this induction, indicating that ASK1-p38 regulates the expression of hBD1-3 and LL37. Furthermore, ASK1-p38 also regulated the expression of Toll-like receptor (TLR) 2 in keratinocytes. Therefore, ASK1-p38 regulates the innate immunity of the skin by forming an immune barrier consisting of hBDs, LL37, and TLR2 during epidermal differentiation.
Skin wound closure is essential for resistance against microbial pathogens, and keratinocyte migration is an important step in skin wound healing. Since LL-37 is upregulated at skin wound sites, LL-37 may induce keratinocyte migration. In this study, we found that LL-37 induced keratinocyte migration via HB-EGF-mediated transactivation of EGFR. This study strongly suggests that LL-37 closes the skin wound by induction of keratinocyte migration.
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[Journal Article] SOCS3/CIS3 negative regulation of STAT3 in HGF-induced keratinocyte migration.2005
Author(s)
Tokumaru S, Sayama K, Yamasaki K, Shirakata Y, Hanakawa Y, Yahata Y, Dai X, Tohyama M, Yang L, Yoshimura A, Hashimoto K.
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Journal Title
Biochem Biophys Res Commun. 327
Pages: 100-105
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Heparin-binding EGF-like growth factor accelerates keratinocyte migration and skin wound healing.2005
Author(s)
Shirakata Y, Kimura R, Nanba D, Iwamoto R, Tokumaru S, Morimoto C, Yokota K, Nakamura M, Sayama K, Mekada E, Higashiyama S, Hashimoto K
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Journal Title
J Cell Sci 118
Pages: 2363-2370
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] New mechanisms of skin innate immunity : ASK1-mediated keratinocyte differentiation regulates the expression of β-defensins, LL37, and TLR2.2005
Author(s)
Sayama K, Komatsuzawa H, Yamasaki K, Shirakata Y, Hanakawa Y, Ouhara K, Tokumaru S, Dai X, Tohyama M, Ten Dijke P, Sugai M, Ichijo H, Hashimoto K
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Journal Title
Eur J Immun 35
Pages: 1886-1895
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Microbubble-enhanced ultrasound for gene transfer into living skin equivalents.2005
Author(s)
Yang L, Shirakata Y, Tamai K, Dai X, Hanakawa Y, Tokumaru S, Yahata Y, Tohyama M, Shiraishi K, Nagai H, Wang X, Murakami S, Sayama K, Kaneda Y, Hashimoto K
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Journal Title
J Dermatol Sci. 40
Pages: 105-114
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] dsRNA-mediated innate immunity of epidermal keratinocytes.2005
Author(s)
Tohyama M, Dai X, Sayam K, Yamasaki K, Shirakata Y, Hanakawa Y, Tokumaru S, Yahata Y, Yang L, Nagai H, Takashima A, Hashimoto K
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Journal Title
Biochem Biophys Res Commun. 335
Pages: 505-511
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Induction of keratinocyte migration via transactivation of the EGF receptor by the antimicrobial peptide LL-37.2005
Author(s)
Tokumaru S, Sayama K, Shirakata Y, Komatsuzawa H, Ouhara K, Hanakawa Y, Yahata Y, Dai X, Tohyama M, Nagai H, Yang L, Higashiyama S, Yoshimura A, Sugai M, Hashimoto K
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Journal Title
J Immunol. 175
Pages: 4662-4668
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Susceptibilities of periodontopathogenic and cariogenic bacteria to antibacterial peptides, {beta}-defensins and LL37, produced by human epithelial cells.2005
Author(s)
Ouhara K, Komatsuzawa H, Yamada S, Shiba H, Fujiwara T, Ohara M, Sayama K, Hashimoto K, Kurihara H, Sugai M.
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Journal Title
J Antimicrob Chemother. 55
Pages: 888-896
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] SOCS1 negative feedback of STAT1 activation is a key pathway in the dsRNA-induced innate immune response of human keratinocytes.
Author(s)
Dai X, Sayama K, Yamasaki K, Tohyama M, Shirakata Y, Hanakawa Y, Tokumaru S, Yahata Y, Yang L, Yoshimura A, Hashimoto K
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Journal Title
J Invest Dermatol (in press). (in press). (in press)
Description
「研究成果報告書概要(欧文)」より
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