Soluble IL-1RAcP proteins as inhibitors of inflammation

可溶性 IL-1RAcP 蛋白作为炎症抑制剂

基本信息

批准号：
7193819
负责人：
LISELOTTE E JENSEN
金额：
$ 7.88万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7193819
关键词：
Acne Agonist Alternative Splicing Anti-Inflammatory Agents Anti-inflammatory Area Arthritis Awareness B-Lymphocytes Binding Biological Biological Assay Cells Cellular Stress Response Chronic Complex Condition Data Disease Enzyme-Linked Immunosorbent Assay Epithelial Epithelial Cells Event Family Family member Functional disorder Gene Activation Gene Expression Genes Goals Homeostasis Human Immune Immune response Immune system Individual Infection Inflammation Inflammatory Inflammatory Response Interleukin-1 Interleukin-18 Interleukins Knowledge Lead Leukocytes Mediating Mediator of activation protein Membrane Messenger RNA Molecular Molecular Profiling Musculoskeletal Pathway interactions Pattern Phenotype Play Polymerase Chain Reaction Principal Investigator Production Protein Isoforms Proteins Psoriasis Recombinants Recruitment Activity Relative (related person)Research Project Grants Resolution Reverse Transcriptase Polymerase Chain Reaction Reverse Transcription Role Signal Transduction Skin Stimulus Testing Therapeutic Therapeutic Agents Tissues Toll-like receptors Transcript Variant Work biological adaptation to stress cell growth regulation chemokine cytokine inhibitor/antagonist interleukin-1 receptor accessory protein keratinocyte leukocyte activation macrophage member monocyte novel pathogen protein function receptor research study response

项目摘要

DESCRIPTION (provided by applicant): Skin inflammation involves local production of cytokines, which mediate recruitment of leucocytes and altered gene expression and cellular phenotypes of keratinocytes and other cells residing in the skin. lnterleukin-1 (IL-1) is an important mediator of local and systemic inflammation. IL-1 acts via a receptor complex involving the IL-1 receptor type I (IL-1RI) and membrane bound IL-1 receptor accessory protein (mlL-1 RAcP). A soluble isoform of IL-1 RAcP (slL-1 RAcP) appears to be an inhibitor of IL-1 signaling. The Principal Investigator has identified a novel soluble isoform of IL-1 RAcP, slL-1RAcP-(3, which has a unique C-terminus. Recently discovered cytokines, related to IL-1, appear to have activities similar to IL-1, but act via a different membrane receptor, IL-1 receptor related protein 2 (IL-1Rrp2). IL-1Rrp2 is primarily expressed in epithelial tissues, and preliminary data suggests that different IL-1 family members orchestrate distinct immune responses by inducing distinct cytokine expression profiles in primary human keratinocytes. Interestingly, IL-1 Rrp2 also utilizes mlL-1 RAcP for intracellular signaling. The primary hypothesis is that the two different isoforms of soluble IL-1 RAcP, slL-1 RAcP and slL-1 RAcP-|3, may inhibit the activities of all IL-1 family members or a sub-set of these. Furthermore, proportional expression of the three different isoforms of IL-1 RAcP may determine cellular responses to inflammatory stimuli. Since IL-1Rrp2 is primarily expressed in epithelial cells the involved mechanism may play a significant role in skin homeostasis and inflammation. ecombinant soluble IL-1 RAcP proteins will be expressed and purified. Human keratinocytes will be treated with agonist IL-1 family members and activation of gene expression will be examined using quantitative reverse transcription PCR and ELISA assays. Activities of the two soluble IL-1 RAcP isoforms will be examined in co-treatment experiments with individual cytokines. Expression of the three different IL-1 RacP isoforms and the IL-1 family members in keratinocytes will be determined following treatments with known modulators of IL-1 RAcP proportional expression and members of the IL-1 family. This project will provide novel information about the function(s) of the novel IL-1 related cytokines and the two soluble IL-1 RacP isoforms. The ultimate goals are to elucidate molecular mechanisms regulating inflammation, identify defective pathways in diseases and utilize this knowledge to develop novel anti-inflammatory therapies. of this work would greatly benefit arthritic and musculoskeletal therapeutic areas.

描述（由申请人提供）：皮肤炎症涉及细胞因子的局部产生，可介导角质形成细胞和其他居住在皮肤中的其他细胞的基因表达和细胞表型改变。 lnterleukin-1（IL-1）是局部和全身炎症的重要介体。 IL-1通过涉及I型I型（IL-1RI）和膜结合的IL-1受体辅助蛋白（MLL-1 RACP）的受体复合物起作用。 IL-1 RACP（SLL-1 RACP）的可溶性亚型似乎是IL-1信号传导的抑制剂。首席研究者已经确定了IL-1 RACP SLL-1RACP-（3，具有独特的C-末端。最近发现的与IL-1相关的细胞因子的新型溶剂化亚型（3初步数据表明，不同的IL-1家族成员通过诱导原代人角质形成细胞中的独特的细胞因子表达谱，有趣的是，IL-1 RRP2也利用MLL-1 RACP也利用了细胞内信号。在所有IL-1家族成员或其中的子集中，IL-1 RACP的三种不同同工型的表达可能会确定IL-1RRP2的细胞反应。将表达和纯化生态组合可溶性IL-1 RACP蛋白。人角质形成细胞将用激动剂IL-1家族成员治疗，并将使用定量逆转录PCR和ELISA分析来检查基因表达的激活。在与单个细胞因子的共同处理实验中，将检查两个可溶性IL-1 RACP同工型的活性。在使用已知的IL-1 RACP比例表达的已知调节剂和IL-1家族的成员处理后，将确定三种不同的IL-1 RACP同工型和角质形成细胞中IL-1家族成员的表达。该项目将提供有关新型IL-1相关细胞因子和两个可溶性IL-1 RACP同工型功能的新信息。最终目标是阐明调节炎症的分子机制，确定疾病中有缺陷的途径，并利用这些知识来开发新型的抗炎疗法。这项工作将极大地使关节炎和肌肉骨骼治疗区域受益。