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

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向细胞核传递信号。STAT3在细胞增殖、迁移等生物学功能中发挥着重要作用。细胞因子信号抑制因子(SOCs)调节细胞因子信号的强度。SOCS3被多种细胞因子和其他刺激物强烈诱导。SOCS3的抑制作用已被证明是相对特异的STAT3。因此，我们研究了SOCS3在表皮角质形成细胞中的作用。由于种系靶向SOCS3基因导致胚胎死亡，我们使用Cre/loxP技术和角蛋白5启动子相结合的方法获得了角质形成细胞特异性SOCS3缺陷小鼠(KS-SOCS3-/-小鼠)。KS-SOCS3-/-小鼠存活，出生时皮肤看起来正常。KS-SOCS3-/-小鼠皮肤未见组织学改变，但20周后，皮肤呈红色鳞片状，…出现角化过度病变。一些小鼠的耳朵、尾巴和背部皮肤较多。皮损组织学检查显示明显增生，网脊延长，颗粒层消失，角化不全。这些表型和组织学表现与人类牛皮癣皮损有很大的相似之处。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-/-小鼠最早在剥离后4天就出现鳞片状皮损，而野生型小鼠表现出轻微的表型。在KS-SOCS3-/-小鼠中发现的表型持续到剥离后14天，而野生型小鼠没有明显的临床表型。胶带剥离诱导的KS-SOCS3-/-小鼠皮损也表现出人类银屑病的组织学特征。KS-SOCS3-/-小鼠表皮角质形成细胞Ki67呈强阳性。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的内源性抑制因子SOCS3的缺失导致了银屑病的临床表型。较少

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