IL-18 in rheumatoid inflammation and angiogenesis

IL-18 在类风湿炎症和血管生成中的作用

• 批准号: 6941299
• 负责人: ALISA E KOCH
• 金额: $ 28.45万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6941299
• 关键词: SDS polyacrylamide gel electrophoresis; angiogenesis; angiogenesis factor; autoradiography; cell adhesion molecules; chemokine; clinical research; enzyme linked immunosorbent assay; flow cytometry; gene expression; helper T lymphocyte; human tissue; immunoprecipitation; inflammation; laboratory mouse; leukocyte activation /transformation; nuclear factor kappa beta; pathologic process; polymerase chain reaction; protein kinase; rheumatoid arthritis; synovial fluid; synovial membrane; thin layer chromatography; tissue /cell culture; vascular cell adhesion molecule; western blottings

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a prototype inflammatory disease characterized by leukocyte infiltration, which is in large part mediated by chemokines and cellular adhesion molecules. Angiogenesis, or new blood vessel growth, is integral to the development of the inflamed RA synovial tissue (ST) pannus. Without angiogenesis, leukocyte infiltration could not occur. A novel cytokine, interleukin (IL)-I8 has recently been identified. This cytokine stimulates T helper 1 (Thl) cytokine production by T cells. The functional role of this cytokine in RA is still unclear. In this proposal we hypothesize that IL-18 contributes to RA joint inflammation and angiogenesls. We plan to determine the mechanism by which IL-18 serves as an inducer of chemokine production in RA ST fibroblasts and whether this chemokine production occurs via G proteins, src family kinases, mitogen activated kinases, or PI3 kinases. Besides chemokines, cellular adhesion molecules are needed for leukocyte ingress into inflamed STs. We will examine whether IL-18 induces leukocyte-endothelial adhesion molecule expression and the mechanism of this expression. Finally, leukocyte ingress would not take place without angiogenesis. We will ascertain the mechanism by which IL-18 mediates angiogenesis in RA in terms of the endothelial signaling pathways, which are activated. Finally, we will study IL-18 gene-deficient mice to determine if they have impaired angiogenesis. We will employ these gene deficient animals bred on an arthritis-susceptible strain to examine whether arthritis associated angiogenesis in the joints is decreased. Several years ago cytokine modulation as a therapy for RA was simply a hope. Currently, cytokine modulation aimed at ablating tumor necrosis factor-alpha is one of the best treatments available for RA and IL-1 targeting is beginning to be used therapeutically. IL-18, by virtue of its ability to induce chemokine release, adhesion molecule expression, and angiogenesis, appears to be a very critical cytokine to target. Our proposal should answer some key questions, which may determine the ability of IL-18 to be a therapeutic target in RA.

描述（由申请人提供）： 类风湿关节炎（RA）是一种以白细胞浸润为特征的原型炎症性疾病，在很大程度上是由趋化因子和细胞粘附分子介导的。血管生成或新血管生长是发炎的RA滑膜组织（ST）Pannus的发展不可或缺的。没有血管生成，就无法发生白细胞浸润。最近已经确定了一种新型的细胞因子，白介素（IL）-i8。该细胞因子刺激T细胞产生T辅助1（THL）细胞因子。该细胞因子在RA中的功能作用尚不清楚。在此提案中，我们假设IL-18有助于RA关节炎症和血管生成。我们计划确定IL-18作为RA ST成纤维细胞中趋化因子产生的诱导剂的机制，以及该趋化因子的产生是通过G蛋白，SRC家族激酶，有丝分裂原活化激酶还是PI3激酶发生的。除趋化因子外，白细胞还需要细胞粘附分子进入发炎的ST。我们将检查IL-18是否诱导白细胞 - 内皮粘附分子表达和该表达的机制。最后，没有血管生成不会进行白细胞入口。我们将确定IL-18通过激活的内皮信号通路介导RA中的血管生成的机制。最后，我们将研究IL-18基因缺陷型小鼠，以确定它们是否损害了血管生成。我们将采用这些缺乏关节炎菌株繁殖的基因不足动物，以检查关节中关节炎的血管生成是否减少。几年前，细胞因子调节作为RA疗法只是一种希望。当前，旨在消除肿瘤坏死因子-Alpha的细胞因子调节是可用于RA的最佳治疗方法之一，而IL-1靶向开始使用治疗。 IL-18，由于其诱导趋化因子释放，粘附分子表达和血管生成的能力似乎是靶向靶向的非常关键的细胞因子。我们的建议应该回答一些关键问题，这可能决定IL-18成为RA治疗靶点的能力。