Role of keratinocyte apoptosis and differentiation regulated by ASK1 in wound healing

ASK1调控角质形成细胞凋亡和分化在伤口愈合中的作用

• 批准号: 13670889
• 负责人: SAYAMA Koji
• 金额: $ 2.62万
• 依托单位: Ehime University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670889/
• 关键词: skin; wound healing; differentiation; ASK1; MAP kinase; PI3 kinase; bacteria; apoptosis; p38MAP kinase; 表皮; 角化細胞; トランスジェニック

Apoptosis and differentiation of epidermal keratinocyte play an important role in skin wound healing. Since, ASK1 regulates apoptosis and differentiation of keratinocyte, ASK1 may regulate skin wound healing. In addition to ASK1, PI3 kinase, which also regulates apoptosis, may contributes skin wound healing. After damage of the cultured human keratinoycte, JNK and p38 MAP kinase activity was analyzed. The damage activated the JNK and p38 MAP kinase, suggesting the activation of ASK1-JNK, and -p38 MAP kinase cascades. Bacterial infection retards skin wound healing. The effect of bacterial infection on keratinocyte was analyzed. Contact of bacteria to cultured keratinocyte induced the production of anti-microbacterial peptides. Next we analyzed whether PI3 kinase regulate keratinoycte differentiation. Differentiation induced the expression of K1 and K10 mRNA. This induction was reduced by expression of active PI3 kinase, indicating that PI3 kinase regulates skin wound healing by apoptosis and differentiation. After formation of wound on the back of mouse, the process of wound healing was histological observed.Keratinocyte apoptosis was detected with TUNEL method on the surrounding skin. Immunohistochemical staining showed that the expression of ASK1 on the epidermal keratinocytes. In conclusion, ASK1 plays an important role in skin wound healing by regulating apoptosis and differentiation of epidermal keratinoycte.

表皮角质形成细胞的凋亡和分化在皮肤创伤愈合过程中起重要作用。由于ASK 1调节角质形成细胞的凋亡和分化，因此ASK 1可能调节皮肤创伤愈合。除了ASK 1，PI 3激酶也调节细胞凋亡，可能有助于皮肤伤口愈合。损伤培养的人角质形成细胞后，分析JNK和p38 MAP激酶活性。损伤激活了JNK和p38 MAP激酶，表明激活了ASK 1-JNK和-p38 MAP激酶级联。细菌感染延缓皮肤伤口愈合。分析细菌感染对角质形成细胞的影响。细菌与培养的角质形成细胞接触诱导抗微生物肽的产生。接下来，我们分析了PI 3激酶是否调节角质形成细胞分化。分化诱导K1和K10 mRNA表达。活性PI 3激酶的表达降低了这种诱导，表明PI 3激酶通过细胞凋亡和分化调节皮肤伤口愈合。在小鼠背部形成创面后，组织学观察创面愈合过程，TUNEL法检测创面周围皮肤角质形成细胞凋亡情况。免疫组织化学染色显示，ASK 1在表皮角质形成细胞上有表达。结论：ASK 1通过调节表皮角质形成细胞的凋亡和分化，在皮肤创伤愈合中发挥重要作用。

项目成果

Tohyama M, Shirakara Y, Yamasaki K, Sayama K, Hashimoto K.: "Differentiated keratinocytes are responsible for TNF-alpha regulated production of macrophage inflammatory protein 3alpha/CCL20, a potent chemokine for Langerhans cells"J Dermatol Sci.. 27(2). 1

Tohyama M、Shirakara Y、Yamasaki K、Sayama K、Hashimoto K.：“分化的角质形成细胞负责 TNF-α 调节巨噬细胞炎症蛋白 3alpha/CCL20 的产生，这是朗格汉斯细胞的有效趋化因子”J Dermatol Sci.. 27(2

M.Tohyama: "Re1A-associated Inhibitor (RA1) Regulates NP-κB in Differentiated Keratinocytes"J. Invest. Dermatol.. 117. 407 (2001)

M. Tohyama：“Re1A 相关抑制剂 (RA1) 调节分化角质形成细胞中的 NP-κB”J. Invest.. 117. 407 (2001)

Yamasaki K, Hanakawa Y, Tokumaru S, Shairakata Y, Sayama K, Hanada T, Yoshimura A, Hashimoto K: "SOCS1/JAB and SOCS3/CIS negatively rgulate the STATs signaling pathway in normal human epidermal keratinocytes"J Invest. Dermatol.. (in press).

Yamasaki K、Hanakawa Y、Tokumaru S、Shairakata Y、Sayama K、Hanada T、Yoshimura A、Hashimoto K：“SOCS1/JAB 和 SOCS3/CIS 负向调节正常人表皮角质形成细胞中的 STATs 信号通路”J Invest。

Shirakata Y, Tamai K, Nakaoka H, Tokumaru S, Sayama K, Murakami S, Hashimoto K: "Severe Palmo-plantar hyperkeratosis in koebner epidermolysis bullosa simp"J Dermatol.. (in press).

Shirakata Y、Tamai K、Nakaoka H、Tokumaru S、Sayama K、Murakami S、Hashimoto K：“Koebner 大疱性表皮松解症中的严重掌跖角化过度”J Dermatol ..（正在印刷中）。

Ii, M., Sayama, K., Tohyama.M., Hashirnoto, K..: "A case of cold-dependent exercise-induced anaphylaxis."Br J Dermatol.. 147(2). 368-370 (2002)

Ii, M.、Sayama, K.、Tohyama.M.、Hashirnoto, K..：“一例寒冷依赖性运动引起的过敏反应。”Br J Dermatol.. 147(2)。