IL-18 in rheumatoid inflammation and angiogenesis

描述(由申请人提供)： 类风湿关节炎(RA)是以白细胞浸润为特征的炎症性疾病，在很大程度上是由趋化因子和细胞黏附分子介导的。血管生成或新血管生长是炎症的类风湿关节炎滑膜组织(ST)血管膜形成过程中不可或缺的一部分。如果没有血管生成，就不会有白细胞的渗透。最近发现了一种新的细胞因子--白介素I8。这种细胞因子刺激T细胞产生辅助性T细胞因子。这种细胞因子在类风湿关节炎中的作用尚不清楚。在这项建议中，我们假设IL-18参与RA关节炎症和血管生成。我们计划确定IL-18在RA ST成纤维细胞中作为趋化因子产生诱导剂的机制，以及这种趋化因子的产生是通过G蛋白、src家族激酶、丝裂原激活的激酶还是PI3激酶来实现的。除了趋化因子外，白细胞进入炎症的STS还需要细胞黏附分子。我们将研究IL-18是否诱导白细胞-内皮细胞黏附分子的表达以及这种表达的机制。最后，如果没有血管生成，白细胞就不会进入。我们将通过激活的内皮信号通路来确定IL-18介导RA血管生成的机制。最后，我们将研究IL-18基因缺陷的小鼠，以确定它们是否损害了血管生成。我们将利用这些基因缺失的动物培育出一种关节炎易感品系，以检查关节中与关节炎相关的血管生成是否减少。几年前，细胞因子调节作为治疗类风湿性关节炎的方法只是一个希望。目前，针对肿瘤坏死因子-α的细胞因子调节是治疗类风湿关节炎的最佳方法之一，IL-1靶向已开始用于治疗。IL-18具有诱导趋化因子释放、黏附分子表达和血管生成的能力，是靶向治疗的关键细胞因子。我们的建议应该回答一些关键问题，这些问题可能决定IL-18作为RA治疗靶点的能力。

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.