Research of the fimction of SOCS3 in the pathogenesis ofpscriasis using keratinocyte specific SOCS3 knozkout mice

角化细胞特异性SOCS3基因敲除小鼠研究SOCS3在牛皮癣发病机制中的作用

• 批准号: 18390314
• 负责人: HASHIMOTO Koji
• 金额: $ 11.14万
• 依托单位: Ehime University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390314/
• 关键词: psoriasis; keratinocytes; SOCS3; STAT3; keratinocyte-specific knockout mouse; regeneration; RT-PCR; epidermal thickenin

STAT3 is a latent cytoplasmic protein that conveys signals to the nucleus upon stimulation with IL-6, EGF and many other growth factors. STAT3 plays critical roles in biological function such as cell proliferation, migration and so on. Suppressors of cytokine signaling (SOCS) regulate the strength of cytokine signals. SOCS3 is strongly induced by a variety of cytokines and other stimulators. The suppressive effect of SOCS3 has been shown to be relatively specific to STAT3. Therefore we investigated the role of SOCS3 in epidermal keratinocytes. Since germline targeting of the SOCS3 gene resulted in embryonic lethality, we generated keratinocyte-specific SOCS3-deficient mice (KS-SOCS3-/-mice) using Cre/loxP technology in combination with the keratin 5 promoter. KS-SOCS3-/-mice were viable and their skin appeared normal at birth. No histological alterations were found in skin of KS-SOCS3-/-mice, however, after 20 weeks, their skin was red and scaly, hyperkeratotic lesions developed in the … More ear, tail and the back skin in some mice. Histological analysis of skin lesions showed a marked hyperplasia, elongation of rete ridge, loss of granular layer and parakeratosis. These phenotype and histology show a strong resemblance to human psoriasis lesions. Next we utilized tape stripping which is a mild form of epidermal injury. KS-SOCS3-/-mice developed scaly lesions as early as 4days after stripping, whereas wild type mice showed a mild phenotype. The phenotype found in KS-SOCS3-/-mice prolonged until 14 days after stripping when wild type mice showed no obvious clinical phenotype. Tape stripping-induced lesions of KS-SOCS3-/-mice also showed histological feature of human psoriasis. Keratinocytes in the epidermis of KS-SOCS3-/-mice were highly positive for Ki67. Phosphorylated STAT3 staining was strong in KS-SOCS3-/-mice compared to wild type mice. In conclusion, loss of SOCS3, an endogenous inhibitor of STAT3, in epidermal keratinocytes leads to clinical phenotype of human psoriasis. Less

STAT3 是一种潜在的细胞质蛋白，在 IL-6、EGF 和许多其他生长因子的刺激下将信号传递到细胞核。 STAT3在细胞增殖、迁移等生物学功能中发挥着关键作用。细胞因子信号传导抑制因子 (SOCS) 调节细胞因子信号的强度。 SOCS3 受到多种细胞因子和其他刺激物的强烈诱导。 SOCS3 的抑制作用已被证明对 STAT3 具有相对特异性。因此我们研究了 SOCS3 在表皮角质形成细胞中的作用。由于 SOCS3 基因的种系靶向导致胚胎致死，因此我们使用 Cre/loxP 技术结合角蛋白 5 启动子生成了角化细胞特异性 SOCS3 缺陷小鼠 (KS-SOCS3-/-小鼠)。 KS-SOCS3-/-小鼠能够存活，出生时皮肤看起来正常。 KS-SOCS3-/-小鼠的皮肤没有发现组织学改变，然而，20周后，它们的皮肤呈红色和鳞状，一些小鼠的耳朵、尾巴和背部皮肤出现过度角化病变。皮损组织学分析显示明显增生、网状嵴伸长、颗粒层缺失和角化不全。这些表型和组织学与人类牛皮癣病变非常相似。接下来我们使用胶带剥离，这是一种轻微的表皮损伤形式。 KS-SOCS3-/-小鼠早在剥离后4天就出现鳞状病变，而野生型小鼠则表现出轻微的表型。 KS-SOCS3-/-小鼠中发现的表型持续到剥离后14天，而野生型小鼠则没有表现出明显的临床表型。 KS-SOCS3-/-小鼠的胶带剥离诱导的病变也显示出人类牛皮癣的组织学特征。 KS-SOCS3-/-小鼠表皮的角质形成细胞对 Ki67 呈高度阳性。与野生型小鼠相比，KS-SOCS3-/-小鼠的磷酸化 STAT3 染色较强。总之，表皮角质形成细胞中 STAT3 的内源性抑制剂 SOCS3 的缺失导致人类银屑病的临床表型。较少的

项目成果

TAK I is essential for differentiation and the prevention of apoptosis in epidermis

TAK I 对于表皮分化和预防细胞凋亡至关重要

• 发表时间: 2006
• 期刊: J Biol Chem 281
• 作者: Sayama;K;Hanakawa;Y;Nagai;H;Shiralcata;Y;Dai;X;Hirakawa;S;Tokumaru;S;Tohyama;M;Yang;L;Sato;S;Shizuo;A;Hashimoto;K
• 通讯作者: K

PPARγ/C/EBPalpha signaling pathway plays a key role in 1,25-dihydroxyvitamin D3-induced keratinocyte differentiation.

PPARγ/C/EBPα信号通路在1,25-二羟基维生素D3诱导的角质形成细胞分化中发挥关键作用。

• 发表时间: 2006
• 作者: Y Shirakata;X Dai;S Tokumaru;Y Hanakawa;M Tohyama;L Yang;K Sayama;and K Hashimoto
• 通讯作者: and K Hashimoto

PPARgamma is an important transcription factor in lalpha,25-dihyclroxyvitamin 03-induced involucrin expression

PPARgamma 是 lalpha,25-二羟维生素 03 诱导的外皮蛋白表达中的重要转录因子

• 发表时间: 2008
• 期刊: I Dermatol Sci 50
• 作者: Dai;X;Sayama;IC;Shirakata;Y;Tokunaru;S;Yang;L;Tohyama;M;Hirakawa;S;Hanakawa;Y;Hashimoto;K
• 通讯作者: K

A new skin equivalent using de-epithelialized amnion membrane

使用去上皮羊膜的新皮肤等同物

• 发表时间: 2007
• 作者: Shirakata Y;Yang L;Hashimoto K
• 通讯作者: Hashimoto K

Human corneal epithelial cell proliferation by epiregulin and its cross-induction by other EGF family members

上皮调节蛋白对人角膜上皮细胞的增殖及其与其他EGF家族成员的交叉诱导

• 发表时间: 2007
• 期刊: Mol. Vision 13
• 作者: Morita;S.;Shirakata;Y.;Shiraishi;A.Kadota;Y.;Hashimoto ;K.;Higashiyama,S.;Ohashi;Y.
• 通讯作者: Y.