THE ROLE OF IL-31 IN TH2 CYTOKINE-DRIVEN SYSTEMIC SCLEROSIS

描述(申请人提供)：系统性硬化症(SSC)仅在美国就影响大约20万人。SSc的治疗是困难的、不完整的，也不是根治的。 Th2细胞因子极化的T细胞反应被认为是介导SSC炎症、自身抗体产生和纤维化发展的介质，但对Th2细胞因子驱动的SSC免疫病理过程中涉及的特定分子仍有很大的认识差距。白介素31(IL-31)是一种新发现的细胞因子，由活化的Th2 T细胞产生，在小鼠皮肤中过度产生IL-31可引起严重的瘙痒、脱发和皮肤损害，类似于SSC。IL-31信号主要通过由IL-31受体α(IL-31RA)和肿瘤抑素M受体β(OSMR？)组成的异二聚体受体复合体传递。我们实验室的初步数据显示，在博莱霉素诱导的SSc皮损中，IL-31、IL-31RA和OSMR？的表达增加。此外，关键的Th-2细胞因子IL-4和IL-13直接增加炎症巨噬细胞中IL-31RA的表达。这些发现支持我们的中心假设，即Th2细胞因子和IL-31-IL-31RA相互作用在SSC的免疫病理中起重要作用。本研究的目的是探讨IL-4和IL-13在体内对IL-31RA亚单位表达的调节作用以及IL-31在SSC免疫病理中的作用。我们的长期目标是了解Th2细胞因子和IL-31-IL-31RA的相互作用如何在SSc中用于预防和治疗目的。这一假说将通过追求两个特定的目标来验证：1)利用博莱霉素诱导的SSC小鼠模型，确定IL-4和IL-13对IL-31RA表达的分子调控；以及2)确定IL-31-IL-31RA相互作用在SSC免疫病理中的作用。在第一个目标下，我们将在博莱霉素诱导的SSC小鼠模型中验证Th2细胞因子、IL-4和IL-13调节皮肤细胞IL-31RA表达的假设。这一目标将建立参与IL-31和IL-31RA表达的细胞和Th2细胞因子信号通路。第二个目的是比较野生型和IL-31RA缺陷小鼠在博莱霉素诱导的SSC过程中疾病表型的演变，包括炎症、自身抗体产生和皮肤纤维化。这一目的将为抑制SSC中IL-31-IL-31RA相互作用的潜在治疗益处提供概念证据。该方法是创新的，通过测试IL-4、IL-13和IL-31之间的分子相互作用以及它们的病理皮肤反应，使用博莱霉素诱导的SSC和基因敲除小鼠的模型。这项拟议的研究意义重大，因为这项研究的完成将增加我们对导致SSC的机制的了解，并将导致更好的治疗、治愈或预防。

DESCRIPTION (provided by applicant): Systemic sclerosis (SSc) affects approximately 200,000 individuals in the USA alone. Treatment for SSc is difficult, incomplete, and not curative. Th2-cytokine polarized T cell responses are postulated to mediate inflammation, auto-antibody production and development of fibrosis in SSc, yet there remains a wide knowledge gap on specific molecules involved in the Th2 cytokine-driven immunopathology of SSc. Interleukin- 31 (IL-31) is a newly identified cytokine produced by activated Th2 T cells and overproduction of IL-31 in mouse skin has been shown to cause severe pruritus, alopecia and skin lesions similar to those seen in SSc. IL-31 signals exclusively through a heterodimeric receptor complex consisting of IL-31 receptor alpha (IL-31RA) and oncostatin M receptor beta (OSMR¿). Preliminary data from our laboratory show elevated expression of IL-31, IL-31RA and OSMR¿ in skin lesions of bleomycin-induced SSc. In addition, key Th-2 cytokines IL-4 and IL-13 directly increased IL-31RA expression in inflamed macrophages. These findings support our central hypothesis that Th2 cytokines and IL-31-IL-31RA interactions play an essential role in the immunopathology of SSc. The objective of this application is to identify the in vivo regulation of the IL-31RA subunit expression by IL-4 and IL-13 and the role of IL-31 in the immunopathology of SSc. Our long-term goal is to understand how the Th2 cytokines and IL-31-IL-31RA interactions can be manipulated for preventive and therapeutic purposes in SSc. This hypothesis will be tested by pursuing two specific aims: 1) Determine the molecular regulation of IL-31RA expression by IL-4 and IL-13 using a mouse model of bleomycin-induced SSc; and 2) Identify the role of IL-31-IL-31RA interactions in the immunopathology of SSc. Under the first aim, we will test the hypothesis that the Th2 cytokines, IL-4 and IL-13 regulate IL-31RA expression in skin cells in a mouse model of bleomycin-induced SSc. This aim will establish the cells and Th2 cytokine signaling pathways involved in IL-31 and IL-31RA expression. The second aim will compare wild type and IL-31RA deficient mice for the evolution of disease phenotypes including inflammation, auto-antibody production and fibrosis in the skin during bleomycin-induced SSc. This aim will provide proof of concept for the potential therapeutic benefit of inhibiting IL-31-IL-31RA interactions in SSc. The approach is innovative by testing molecular interactions among IL-4, IL-13 and IL-31 and their pathologic skin responses using a mouse model of bleomycin-induced SSc and knock-out mice. The proposed research is significant, because completion of this study will increase our knowledge of the mechanisms causing SSc and will lead to better medical treatments, cure or prevention.