Therapeutic Role for P21 in Suppressing IL-1 Beta Mediated Pathologies

P21 在抑制 IL-1 Beta 介导的病理学中的治疗作用

• 批准号: 8460058
• 负责人: Harris R Perlman
• 金额: $ 31.29万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-07 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8460058
• 关键词: Adoptive Transfer; Adverse effects; Agonist; Apical; Arthritis; Autoimmune Diseases; Biological Markers; Bone Marrow; CDC2 Protein Kinase; CDK2 gene; CDK4 gene; CDKN1A gene; Cartilage; Cell Cycle; Cell Cycle Arrest; Cells; Collaborations; Cyclin-Dependent Kinases; Data; Degenerative polyarthritis; Development; Disease; Disease Progression; Exhibits; Experimental Arthritis; Flow Cytometry; Goals; Immunoblot Analysis; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Knockout Mice; Ligation; MAPK14 gene; Macrophage Activation; Mediating; Molecular; Morbidity - disease rate; Mus; Pathogenesis; Pathology; Patients; Pattern; Peptides; Phenotype; Phosphorylation; Play; Production; Protein-Serine-Threonine Kinases; Rheumatoid Arthritis; Role; Severity of illness; Signal Pathway; Signal Transduction; Signaling Molecule; Small Interfering RNA; Synovial Fluid; Synovial Membrane; Testing; Therapeutic; Tissues; Toll-like receptors; Translating; base; bone; cytokine; inhibitor/antagonist; macrophage; mimetics; mitogen-activated protein kinase p38; mortality; mouse model; new therapeutic target; novel; oncoprotein p21; prevent; public health relevance; response; small molecule; upstream kinase

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that leads to destruction of bone and cartilage and is associated with increased morbidity and mortality. The mechanism responsible for the persistent inflammation of the synovium is not clear. We were the first to demonstrate that expression of the cyclin dependent kinase (CDK) inhibitor p21(WAF1/CIP1) is reduced in synovial tissue from RA patients compared to osteoarthritis patients. Although one of the major functions of p21 is to arrest the cell cycle, we recently uncovered a novel role for p21 in the suppression of the inflammatory response in macrophages. Macrophages lacking p21 (p21-/-) secrete elevated levels of pro-inflammatory cytokines and display increased markers of activation following ligation by toll like receptor (TLR) agonists. Further, CDK2, a target for p21, is constitutively active in p21-/- macrophages while CDK4 is induced in Wt and p21-/- macrophages following TLR stimulation despite the fact that these cells are terminally differentiated and are withdrawn from the cell cycle. Mice lacking p21 exhibit an enhanced and sustained development of experimental inflammatory arthritis which is associated with markedly increased numbers of macrophages and severe articular destruction. Further, administration of a p21 peptide mimetic suppresses activation of macrophages and prevents development of experimental arthritis. Mechanistically, the increased activation in p21-/- macrophages is associated with the reduction in the activity of the serine/threonine kinase Akt and an increase in the activation of the mitogen-activated protein kinase, p38. Treatment with the p21-peptide mimetic restores Akt and reduces p38 activity in macrophages. Based on these data, we hypothesize that decreased expression of p21 in macrophages leads to the enhanced production of pro-inflammatory molecules mediated by reduced levels of active Akt and increased phosphorylated Ask1 and p38, independent of CDK activation. Taken together, the data anticipated from these studies will be the first to reveal that in macrophages, p21 is apical in determining the fate of the TLR intracellular signaling cascade. Thus, the elucidation of the molecular mechanism governing p21 in macrophages is crucial for understanding the development and persistence of RA and for potential new therapeutic targets for ameliorating RA.

描述（由申请人提供）：类风湿关节炎（RA）是一种炎症自身免疫性疾病，会导致骨骼和软骨的破坏，并且与发病率和死亡率的增加有关。导致滑膜持续炎症的机制尚不清楚。我们是第一个证明细胞周期蛋白依赖性激酶（CDK）抑制剂p21（WAF1/CIP1）的表达与RA患者的滑膜组织中降低的表达相比，与骨关节炎患者相比。尽管p21的主要功能之一是阻止细胞周期，但我们最近发现了p21在抑制巨噬细胞中炎症反应中的新作用。缺乏p21（p21 - / - ）的巨噬细胞分泌促炎性细胞因子的升高水平，并显示出受Toll（例如受体（TLR）激动剂）的连接后，激活的标记增加。此外，CDK2是P21的靶标，在p21 - / - 巨噬细胞中具有组成性活性，而在TLR刺激后，CDK4在WT和P21 - / - 巨噬细胞中诱导，尽管这些细胞实际上是最终分化的，并且已从细胞周期中撤出。缺乏P21的小鼠表现出实验性炎症性关节炎的增强和持续发展，这与巨噬细胞数量显着增加和严重的关节破坏有关。此外，施用P21肽模拟物可抑制巨噬细胞的激活，并防止实验性关节炎的发展。从机械上讲，p21 - / - 巨噬细胞中的激活增加与丝氨酸/苏氨酸激酶AKT活性的降低以及有丝分裂原激活蛋白激酶激活的活性增加有关。用p21肽模拟物处理可恢复AKT并降低巨噬细胞中的p38活性。基于这些数据，我们假设巨噬细胞中p21的表达降低会导致由降低的活性AKT水平介导的促炎性分子的产生，而与CDK激活无关。综上所述，从这些研究中预期的数据将是第一个揭示在巨噬细胞中，p21在确定TLR细胞内信号传导级联的命运方面是顶端。因此，阐明巨噬细胞中p21的分子机制对于理解RA的发展和持久性以及对改善RA的潜在新治疗靶标至关重要。