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：
7663131
负责人：
LISELOTTE E JENSEN
金额：
$ 5.71万
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 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7663131
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 Data Disease Enzyme-Linked Immunosorbent Assay Epithelial Epithelial Cells Event Family Family member Functional disorder 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 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 combat 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，细胞因子介导白细胞的募集并改变角质形成细胞和皮肤中其他细胞的基因表达和细胞表型。白细胞介素-1 (IL-1) 是局部和全身炎症的重要介质。 IL-1 通过涉及 I 型 IL-1 受体 (IL-1RI) 和膜结合 IL-1 受体辅助蛋白 (mlL-1 RAcP) 的受体复合物发挥作用。 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。首席研究员发现了一种新型可溶性 IL-1 RAcP 异构体 slL-1RAcP-(3，它具有独特的 C 末端。最近发现的与 IL-1 相关的细胞因子似乎具有与 IL-1 相似的活性，但通过不同的膜受体发挥作用，IL-1 受体相关蛋白 2 (IL-1Rrp2) 主要在上皮组织中表达，初步数据表明不同的 IL-1 家族成员。通过在原代人角质形成细胞中诱导不同的细胞因子表达谱来协调不同的免疫反应有趣的是，IL-1 Rrp2 还利用 mlL-1 RAcP 进行细胞内信号传导，主要假设是可溶性 IL-1 RAcP（slL-1）的两种不同亚型。 RAcP 和 slL-1 RAcP-|3 可能抑制所有 IL-1 家族成员或其子集的活性。此外，三种不同的比例表达。 IL-1 RAcP 亚型可能决定细胞对炎症刺激的反应，因为 IL-1Rrp2 主要在上皮细胞中表达，因此相关机制可能在皮肤稳态和炎症中发挥重要作用。重组可溶性 IL-1 RAcP 蛋白将被表达和纯化。将用激动剂 IL-1 家族成员处理人角质形成细胞，并使用定量逆转录 PCR 和 ELISA 测定检查基因表达的激活。两种可溶性 IL-1 RAcP 亚型的活性将在与单个细胞因子的共同治疗实验中进行检查。在用已知的IL-1 RAcP比例表达调节剂和IL-1家族成员处理后，将测定角质形成细胞中三种不同IL-1 RacP亚型和IL-1家族成员的表达。该项目将提供有关新型 IL-1 相关细胞因子和两种可溶性 IL-1 RacP 亚型功能的新信息。最终目标是阐明调节炎症的分子机制，识别疾病中的缺陷途径，并利用这些知识开发新型抗炎疗法。这项工作将极大地有益于关节炎和肌肉骨骼治疗领域。