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: 7279466
• 负责人: ALISA E KOCH
• 金额: $ 24.67万
• 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 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7279466
• 关键词: Animals; Arthritis; Biological Assay; Blood Vessels; Breeding; Cell Adhesion; Cell Adhesion Molecules; Cells; Class; Condition; Development; Disease; E-Selectin; Endothelial Cells; Fibroblasts; GTP-Binding Proteins; Genes; Granuloma; Growth; Human; Infiltration; Inflammation; Inflammatory; Integrins; Interleukin-1; Interleukin-18; Interleukins; Joints; Leukocytes; Mediating; Mediator of activation protein; Methods; Mitogen-Activated Protein Kinases; Mitogens; Mus; Pharmaceutical Preparations; Phosphatidylinositols; Phosphotransferases; Porifera; Production; Protein-Serine-Threonine Kinases; Rheumatoid Arthritis; Role; Signal Pathway; Signal Transduction; Site; Synovial Fluid; T-Lymphocyte; Therapeutic; Tissues; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1; Wild Type Mouse; angiogenesis; animal breeding; chemokine; cytokine; day; in vivo Model; matrigel; novel; prototype; research study; src-Family Kinases; therapeutic target

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）： 类风湿性关节炎（RA）是一种以白细胞浸润为特征的原型炎症性疾病，其很大程度上由趋化因子和细胞粘附分子介导。血管生成或新血管生长对于发炎的 RA 滑膜组织 (ST) 血管翳的形成至关重要。如果没有血管生成，白细胞浸润就不会发生。最近发现了一种新的细胞因子——白细胞介素（IL）-I8。该细胞因子刺激 T 细胞产生辅助性 T 细胞 1 (Thl) 细胞因子。这种细胞因子在 RA 中的功能作用仍不清楚。在此提议中，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 成纤维细胞趋化因子产生诱导剂的机制，以及这种趋化因子的产生是否通过 G 蛋白、src 家族激酶、丝裂原激活激酶或 PI3 激酶发生。除了趋化因子外，白细胞进入发炎的 ST 还需要细胞粘附分子。我们将研究IL-18是否诱导白细胞-内皮粘附分子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 基因缺陷小鼠，以确定它们的血管生成是否受损。我们将利用这些在关节炎易感菌株上培育的基因缺陷动物来检查关节炎相关的关节血管生成是否减少。几年前，细胞因子调节作为 RA 的治疗方法还只是一个希望。目前，旨在消除肿瘤坏死因子-α 的细胞因子调节是治疗 RA 的最佳治疗方法之一，而 IL-1 靶向治疗已开始用于治疗。 IL-18 凭借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，这些问题可能决定 IL-18 成为 RA 治疗靶点的能力。

项目成果

New insights in synovial angiogenesis.

• DOI: 10.1016/j.jbspin.2009.05.011
• 发表时间: 2010-01
• 期刊: JOINT BONE SPINE
• 影响因子: 4.2
• 作者: Szekanecz, Zoltan;Besenyei, Timea;Paragh, Gyoergy;Koch, Alisa E.
• 通讯作者: Koch, Alisa E.

H-2g, a glucose analog of blood group H antigen, mediates monocyte recruitment in vitro and in vivo via IL-8/CXCL8.

H-2g 是 H 型血抗原的葡萄糖类似物，通过 IL-8/CXCL8 在体外和体内介导单核细胞募集。

• DOI: 10.2147/oarrr.s36163
• 发表时间: 2012
• 期刊: Open access rheumatology : research and reviews
• 作者: Rabquer,BradleyJ;Hou,Yong;Ruth,JeffreyH;Luo,Wei;Eitzman,DanielT;Koch,AlisaE;Amin,MohammadA
• 通讯作者: Amin,MohammadA

Effect of oxidative stress on protein tyrosine phosphatase 1B in scleroderma dermal fibroblasts.

• DOI: 10.1002/art.34336
• 发表时间: 2012-06
• 期刊: ARTHRITIS AND RHEUMATISM
• 作者: Tsou, Pei-Suen;Talia, Nadine N.;Pinney, Adam J.;Kendzicky, Ann;Piera-Velazquez, Sonsoles;Jimenez, Sergio A.;Seibold, James R.;Phillips, Kristine;Koch, Alisa E.
• 通讯作者: Koch, Alisa E.