PIASy as a negative regulator of Th17 pathway in psoriasis

性状（申请人提供）：免疫力是宿主抵御外来病原体入侵的必要条件。Th 17通路通过上皮细胞、T细胞、树突状细胞之间的动态相互作用而被激活。在正常生理条件下，Th 17通路受到严格控制，以防止慢性炎症。然而，组成性Th 17活化是包括类风湿性关节炎和银屑病在内的许多慢性炎性疾病的共同病理特征。到目前为止，在Th 17炎性疾病中组成性Th 17活化的分子基础仍然很大程度上未知。在这项研究中，我们提供了实验证据，表明PIASy的失活有助于组成性Th 17激活。PIASy缺陷小鼠出现银屑病样表型，局部咪喹莫特治疗后Th 17细胞因子表达增加。更重要的是，PIASy缺乏导致角质形成细胞对TNFα和IL-17 A治疗的应答中IL-23的稳健表达。这是首次证明人银屑病角质形成细胞在TNFα和IL-17 A的作用下产生强大的IL-23。由于IL-23对Th 17活化至关重要，角质形成细胞中Th 17细胞因子诱导的IL-23为通过银屑病角质形成细胞的IL-23过量产生和Th 17 T细胞的IL-17/TNFα细胞因子过量产生形成Th 17活化的正调节环提供了分子基础。在生物化学上，我们已经确定NFκB和STAT 3是PIASy负调控的靶点。由于NFκB和STAT 3是银屑病炎症通路中的主要贡献者，我假设PIASy的失活有助于银屑病中持续的Th 17活化。该假设将通过以下方式进行检验：1）确定PIASy失活的临床相关性及其与IL-23表达和PIASy激活的相关性。 人银屑病中的NF-κ B和STAT 3 ~ 2）确定PIASy在角质形成细胞表达IL 23中的功能作用~ 3）确定PIASy在Th 17 T细胞分化和Th 17 T细胞表达IL 17中的功能作用。分析PIASy分子通路在Th 17调节中的作用，不仅有助于了解银屑病异常炎症的分子基础，而且为银屑病的预后、预防和治疗提供新的策略。

DESCRIPTION (provided by applicant): The immunity is essential for host defense against the invasion of foreign pathogens. The Th17 pathway is activated by dynamic interplays among epithelial cells, T cells, dendritic cells. Under normal physiological conditions, Th17 pathway is tightly controlled to prevent chronic inflammation. However, constitutive Th17 activation is a common pathological feature in many chronic inflammatory diseases including rheumatoid arthritis and psoriasis. So far the molecular basis of constitutive Th17 activation in Th17 inflammatory diseases remains largely unknown. In this study, we have provided experimental evidence to suggest that the inactivation of PIASy contributes to constitutive Th17 activation. PIASy-deficient mice developed psoriasis-like phenotypes and showed increased Th17 cytokine expression in response to topical imiquimod treatment. More importantly, PIASy deficiency resulted in robust expression of IL-23 from keratinocytes in response to the treatment of TNFα and IL-17A. This is the first time to demonstrate that human psoriatic keratinocytes produce robust IL-23 in response to TNFα and IL-17A. As IL-23 is essential for Th17 activation, IL-23 induction by Th17 cytokines in keratinocytes provides a molecular basis for forming a positive regulatory loop of Th17 activation through IL-23 overproduction from psoriatic keratinocytes and IL17/TNFα cytokine overproduction from Th17 T cells. Biochemically, we have identified NFκB and STAT3 as the targets negatively regulated by PIASy. As NFκB and STAT3 are the major contributors in the inflammation circuitry of psoriasis, I hypothesize that inactivation of PIASy contributes to sustained Th17 activation in psoriasis. This hypothesis will be tested by 1) Establish the clinical relevance of PIASy inactivation and its correlation with IL-23 expression and the activation of NF-kB and STAT3 in human psoriasis~ 2) Defining the functional role of PIASy in IL23 expression from keratinocytes~ 3) Defining the functional role of PIASy in Th17 T cells differentiation and IL17 expression from Th17 T cells. The analysis of the PIASy molecular pathway in Th17 regulation will not only enable us to understand the molecular basis of aberrant inflammation in psoriasis, but also provide novel strategies for psoriasis prognosis, prevention and therapy.