IL-18 in rheumatoid inflammation and angiogenesis

描述（由申请人提供）： 类风湿性关节炎（RA）是一种以白细胞浸润为特征的典型炎症性疾病，其主要由趋化因子和细胞粘附分子介导。血管生成或新血管生长是炎症性RA滑膜组织（ST）血管翳发展的组成部分。没有血管生成，白细胞浸润不能发生。白细胞介素（IL）-18是一种新的细胞因子。该细胞因子刺激T细胞产生辅助性T细胞I（Thl）细胞因子。这种细胞因子在RA中的功能作用尚不清楚。在这个提议中，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诱导剂的机制，以及这种趋化因子产生是否通过G蛋白、src家族激酶、促分裂原激活激酶或PI 3激酶发生。除了趋化因子，细胞粘附分子是白细胞进入发炎的ST所必需的。我们将研究IL-18是否诱导白细胞-内皮细胞粘附分子的表达和这种表达的机制。最后，如果没有血管生成，白细胞进入就不会发生。我们将确定的机制，IL-18介导的血管生成在RA的内皮细胞信号通路，这是激活。最后，我们将研究IL-18基因缺陷的小鼠，以确定它们是否有受损的血管生成。我们将使用这些基因缺陷的动物繁殖的关节炎敏感株，以检查是否关节炎相关的关节血管生成减少。几年前，细胞因子调节作为RA的治疗方法只是一种希望。目前，旨在消融肿瘤坏死因子-α的细胞因子调节是可用于RA的最佳治疗方法之一，并且IL-1靶向开始用于治疗。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，似乎是一种非常关键的靶细胞因子。我们的建议应该回答一些关键问题，这可能决定IL-18的能力，在RA的治疗靶点。

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.