【作者】 张斌；

【导师】 王宏伟；

【作者基本信息】 南京大学 ， 基础医学， 2014， 硕士

【摘要】 血红素环氧合酶-1(HO-1)具有抗氧化和抗炎的作用,在皮肤受损及创伤修复中扮演重要的角色。而其抑制炎症的作用机制目前还并不明确。银屑病是一种常见的炎症性皮肤疾病,信号传导与转录激活因子3 (Stat3)的过度激活是诱发银屑病的重要原因。在这一过程中,角质形成细胞的过度增殖与异常分化是引发银屑病的直接因素,而Stat3具有促进增殖以及调节分化的作用,因而可以作为治疗银屑病的靶点。我们的研究利用银屑病小鼠模型发现,HO-1的激动剂能够有效缓解银屑病的病理症状,而细胞模型则证实HO-1的激活能够抑制Thl7相关的细胞因子IL-6及IL-22刺激引起的Stat3的活化,并进一步抑制由此引起的角质形成细胞的过度增殖与异常分化。而我们的结果也证实HO-1对Stat3活化的影响是通过刺激酪氨酸磷酸酶-1的表达来实现的。因此,我们的实验证实了Stat3在银屑病发生发展中扮演的重要角色,以及HO-1作为银屑病治疗靶点的可行性以及作用机制。更多还原

【Abstract】 Heme oxygenase-1 (HO-1), a stress-inducible protein with potential anti-inflammatory effect, has been found playing an important role in skin injury and wound healing, however, its function in cutaneous inflammatory disease, such as psoriasis, was not known. Stat3, a known transcription factor that induces inflammation and regulate cell differentiation, play a key role for the pathogenesis development of psoriasis. Targeting Stat3 may be potentially therapeutic in the treatment of psoriasis. In this paper, we found that activation of HO-1 significantly alleviated the disease related pathogenesis abnormality and then we further address the mechanism why HO-1 exert this immune protection. Our result show that upon HO-1 activator administration or HO-1 over expression, the Th17 related cytokines IL6/IL22 induced Stat3 activation were significantly suppressed, these accompanied with decreased cell proliferation and reverse the abnormal cell proliferation, and very interestingly, our result showed that HO-1 induced Stat3 suppression was mediated through the activation of Protein Tyrosine Phosphatase SHP-1. Our study provide direct evidence showing that HO-1 might be an useful therapeutic target for psoriasis, SHP-1 mediated suppression of Stat3 activation after HO-1 activation might represents a unique molecular mechanisms for regulation of Stat3 activation.更多还原