| Project/Area Number |
15209035
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (A)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Dermatology
|
|---|
| Research Institution | Ehime University |
|---|
Principal Investigator |
HASHIMOTO Koji EHIME UNIVERSITY, SCHOOL OF MEDICINE, PROFESSOR, 医学部, 教授 (00110784)
|
|---|
| 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)
山崎 研志 愛媛大学, 医学部, 助手 (40294798)
|
|---|
| Project Period (FY) |
2003 – 2005
|
| Project Status |
Completed (Fiscal Year 2005)
|
| Budget Amount *help |
¥49,140,000 (Direct Cost: ¥37,800,000、Indirect Cost: ¥11,340,000)
Fiscal Year 2005: ¥13,000,000 (Direct Cost: ¥10,000,000、Indirect Cost: ¥3,000,000)
Fiscal Year 2004: ¥12,480,000 (Direct Cost: ¥9,600,000、Indirect Cost: ¥2,880,000)
Fiscal Year 2003: ¥23,660,000 (Direct Cost: ¥18,200,000、Indirect Cost: ¥5,460,000)
|
|---|
| Keywords | Epidermis / Keratinocyte / Differentiation / Innate Immunity / Toll-like receptor / Anti-microbial peptide / Wound Healing / Virus infection / 創傷治療 / 皮膚 / 表皮角化細胞 / ASK1 / toll-like receptor / MAP kinase / 細菌 / MIP3α / 細胞内シグナル |
|---|
| 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.
|
