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

STAT 3是一种潜在的细胞质蛋白，在IL-6，EGF和许多其他生长因子刺激时将信号传递到细胞核。STAT 3在细胞增殖、迁移等生物学功能中发挥重要作用，细胞因子信号转导抑制因子（SOCS）调节细胞因子信号的强度。SOCS 3受多种细胞因子和其他刺激物的强烈诱导。SOCS 3的抑制作用已显示对STAT 3相对特异。因此，我们研究了SOCS 3在表皮角质形成细胞中的作用。由于SOCS 3基因的生殖系靶向导致胚胎致死，我们使用Cre/loxP技术与角蛋白5启动子组合产生角蛋白细胞特异性SOCS 3缺陷小鼠（KS-SOCS 3-/-小鼠）。KS-SOCS 3-/-小鼠是活的，它们的皮肤在出生时看起来正常。在KS-SOCS 3-/-小鼠的皮肤中没有发现组织学改变，然而，20周后，它们的皮肤变红并有鳞屑，在皮肤中出现角化过度病变。 ...更多信息 在某些小鼠的耳朵、尾巴和背部皮肤中。皮损的组织学分析显示明显增生，网脊延长，颗粒层丢失和角化不全。这些表型和组织学表现出与人类银屑病病变的强烈相似性。接下来，我们使用胶带剥离，这是一种轻度的表皮损伤。KS-SOCS 3-/-小鼠早在剥脱后4d就出现鳞状病变，而野生型小鼠表现出轻度表型。在KS-SOCS 3-/-小鼠中发现的表型延长至剥脱后14天，此时野生型小鼠未显示出明显的临床表型。胶带剥离诱导的KS-SOCS 3-/-小鼠的病变也显示出人类银屑病的组织学特征。KS-SOCS 3-/-小鼠表皮中的角质形成细胞对Ki 67呈高度阳性。与野生型小鼠相比，磷酸化STAT 3染色在KS-SOCS 3-/-小鼠中较强。总之，表皮角质形成细胞中STAT 3的内源性抑制剂SOCS 3的缺失导致人银屑病的临床表型。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