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

IL-31 在 TH2 细胞因子驱动的系统性硬化症中的作用

• 批准号: 8446714
• 负责人: Satish K Madala
• 金额: $ 7.65万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-17 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8446714
• 关键词: Affect; Alopecia; Antibody Formation; Autoantibodies; Binding; Biochemical; Biology; Bleomycin; Blood Vessels; Cells; Clinical; Complex; Cytokine Signaling; Data; Development; Disease; Etiology; Evolution; Fibrosis; Free Radicals; Future; Goals; Hematopoietic; Human; Immune System Diseases; Immune response; Individual; Inflammation; Injury; Interleukin Receptor; Interleukin-13; Interleukin-4; Interleukins; Intervention; Ischemia; Knockout Mice; Knowledge; Laboratories; Lead; Link; Lung; Measurement; Mediating; Medical; Methods; Modeling; Molecular; Mus; OSMR gene; Organ; Oxidative Stress; Pathologic; Pathology; Play; Prevention; Preventive; Preventive Intervention; Production; Pruritus; Receptor Signaling; Regulation; Research; Respiratory physiology; Role; Serum; Signal Pathway; Signal Transduction; Skin; Subcutaneous Injections; Systemic Scleroderma; T cell response; T-Lymphocyte; Testing; Th2 Cells; Therapeutic; Therapeutic Intervention; Time; Validation; cell type; cytokine; disease phenotype; immunopathology; in vivo; indium-bleomycin; innovation; macrophage; mouse model; oncostatin M; public health relevance; receptor; response; skin lesion

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.

描述（由申请人提供）：系统性硬化症（SSc）仅在美国就影响了大约200，000人。SSc的治疗是困难的，不完全的，不能治愈。 Th 2-细胞因子极化的T细胞应答被假定为介导SSc中的炎症、自身抗体产生和纤维化的发展，但是对于参与SSc的Th 2丝氨酸驱动的免疫病理学的特定分子仍然存在广泛的知识缺口。白细胞介素-31（IL-31）是一种新发现的由活化的Th 2 T细胞产生的细胞因子，小鼠皮肤中IL-31的过度产生已显示引起与SSc中所见相似的严重瘙痒、脱发和皮肤病变。IL-31信号仅通过由IL-31受体α（IL-31 RA）和抑瘤素M受体β（OSMR）组成的异二聚体受体复合物传递。我们实验室的初步数据显示，在博来霉素诱导的SSc皮损中，IL-31、IL-31 RA和OSMR？的表达升高。此外，关键Th-2细胞因子IL-4和IL-13直接增加炎症巨噬细胞中IL-31 RA的表达。这些发现支持了我们的中心假设，即Th 2细胞因子和IL-31-IL-31 RA相互作用在SSc的免疫病理学中起重要作用。本申请的目的是鉴定IL-4和IL-13对IL-31 RA亚基表达的体内调节以及IL-31在SSc免疫病理学中的作用。我们的长期目标是了解Th 2细胞因子和IL-31-IL-31 RA相互作用如何在SSc中用于预防和治疗目的。该假设将通过追求两个特定目标来检验：1）使用博来霉素诱导的SSc的小鼠模型确定IL-4和IL-13对IL-31 RA表达的分子调节;和2）鉴定IL-31-IL-31 RA相互作用在SSc的免疫病理学中的作用。在第一个目标下，我们将检验Th 2细胞因子IL-4和IL-13调节博来霉素诱导的SSc小鼠模型中皮肤细胞中IL-31 RA表达的假设。这一目的将建立参与IL-31和IL-31 RA表达的细胞和Th 2细胞因子信号通路。第二个目的是比较野生型和IL-31 RA缺陷小鼠在博来霉素诱导的SSc期间疾病表型的演变，包括炎症，自身抗体产生和皮肤纤维化。这一目标将为抑制SSc中IL-31-IL-31 RA相互作用的潜在治疗益处提供概念证明。该方法是创新的，通过使用博来霉素诱导的SSc和基因敲除小鼠的小鼠模型测试IL-4、IL-13和IL-31之间的分子相互作用及其病理皮肤反应。拟议的研究是重要的，因为完成这项研究将增加我们对导致SSc的机制的了解，并将导致更好的医学治疗，治愈或预防。