Cytokine regulation of RA synoviocyte phenotype

RA滑膜细胞表型的细胞因子调节

• 批准号: 7257922
• 负责人: Lionel B Ivashkiv
• 金额: $ 31.92万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-27 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7257922
• 关键词: Abate; Accounting; Anti-Inflammatory Agents; Anti-inflammatory; Biological Response Modifier Therapy; Cell Surface Receptors; Cells; Cytokine Signaling; Disease; Equilibrium; Exhibits; IL8 gene; Immunosuppressive Agents; Inflammation; Inflammatory; Inflammatory Response; Interferons; Interleukin-1; Interleukin-10; Interleukin-15; Interleukin-6; Mediating; Molecular; Morbidity - disease rate; Pathogenesis; Pathway interactions; Phenotype; Process; Production; Protein Binding; Rate; Regulation; Relative (related person); Research Personnel; Rheumatoid Arthritis; Role; Severities; Signal Pathway; Signal Transduction; Stimulus; Synovial Cell; Synovial Membrane; Synovitis; Transcriptional Regulation; Transduction Gene; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Work; anakinra; chemokine; cytokine; extracellular; human TNF protein; insight; interest; macrophage; novel therapeutics; response

DESCRIPTION (provided by investigator): Cytokines have been implicated in the pathogenesis of several inflammatory diseases, including rheumatoid arthritis (RA). A key role for the inflammatory cytokines tumor necrosis factor (TNF) and interleukin-1 (IL-1) in RA pathogenesis has been demonstrated by the efficacy of biological therapies that block TNF and IL-1 activity. Cytokines other than TNFalpha and IL-I are important in RA pathogenesis, and recently there has been increasing interest in the pathogenic role of cytokines that activate the Jak-STAT signaling pathway, including IL-6, IL-15, and IFNgamma. Immunosuppressive and anti-inflammatory cytokines, including TGFbeta, IL-10, and IL-1RA are highly and consistently expressed during RA synovitis. The idea that the balance between levels of pro- and anti-inflammatory factors is important in regulating inflammation in RA has gained broad acceptance among RA researchers. Our work aims to extend this paradigm to take into account that cellular responsiveness to cytokines is regulated in a dynamic fashion, and that signal transduction crosstalk, synergy, and antagonism among pro- and anti-inflammatory synovial factors will regulate the balance of cytokine activity. We have identified two examples of how cytokine signaling can be modulated by the inflammatory RA synovial microenvironment in ways that can contribute to pathogenesis: 1. Signaling by the potent anti-inflammatory cytokine IL-10 is suppressed in RA synovial macrophages, and can be blocked by inflammatory factors. 2. Expression of Stat1, a pro-inflammatory molecule that mediates cytokine signal transduction and transcriptional regulation, is highly elevated in RA synovial cells. Cells expressing elevated Stat1 are hyper-responsive to activation by low concentrations of IFNgamma and exhibit an altered, hyper-inflammatory response to IL-6. In this application, we propose to delineate the mechanisms by which inflammatory pathways operative in RA synovium suppress IL-10 signaling, and to investigate the functional consequences of elevated Stat1 expression on cell phenotype and cytokine activity in the context of RA pathogenesis. Greater understanding of the molecular mechanisms that regulate IL-10 signaling and Stat1 activity will yield insight into cytokine regulation of RA pathogenesis, and will identify novel therapeutic approaches to manipulate cytokine balance in RA at the level of signal transduction.

描述（由研究者提供）：细胞因子与几种炎性疾病的发病机制有关，包括类风湿性关节炎（RA）。炎症细胞因子肿瘤坏死因子（TNF）和白细胞介素-1（IL-1）在RA发病机制中的关键作用已被阻断TNF和IL-1活性的生物疗法的疗效所证实。除了TNF α和IL-1以外的细胞因子在RA发病机制中是重要的，并且最近对激活Jak-STAT信号传导途径的细胞因子（包括IL-6、IL-15和IFN γ）的致病作用的兴趣越来越大。免疫抑制和抗炎细胞因子，包括TGF β、IL-10和IL-1 RA在RA滑膜炎期间高度且一致地表达。促炎因子和抗炎因子水平之间的平衡在调节RA的炎症中是重要的，这一观点已被RA研究人员广泛接受。我们的工作旨在扩展这种模式，考虑到细胞对细胞因子的反应是以动态方式调节的，并且促炎和抗炎滑膜因子之间的信号转导串扰、协同作用和拮抗作用将调节细胞因子活性的平衡。 我们已经确定了两个例子，细胞因子信号如何可以调节炎症性RA滑膜微环境的方式，可以有助于发病机制：1。在RA滑膜巨噬细胞中，强效抗炎细胞因子IL-10的信号传导受到抑制，并且可以被炎症因子阻断。2. Stat 1是一种介导细胞因子信号转导和转录调节的促炎分子，其表达在RA滑膜细胞中高度升高。表达升高的Stat 1的细胞对低浓度IFN γ的激活反应过度，并表现出对IL-6的改变的超炎症反应。在这个应用中，我们建议描绘的机制，炎症途径在RA滑膜抑制IL-10信号传导，并调查的功能性后果Stat 1表达升高的细胞表型和细胞因子活性的RA发病机制的背景下。更好地了解调节IL-10信号和Stat 1活性的分子机制，将有助于深入了解RA发病机制的细胞因子调节，并将确定新的治疗方法，在信号转导水平上操纵RA中的细胞因子平衡。