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MECHANISMS OF NOVEL ANTI-INFLAMMATORY ACTIONS OF SLPI

SLPI 的新型抗炎作用机制

基本信息

批准号：
7239622
负责人：
Aihao Ding
金额：
$ 33.77万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-06-01 至 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7239622
关键词：
Abbreviations Accounting Acids Affect Anatomy Anti-Inflammatory Agents Anti-inflammatory Attenuated Autoimmune Process Binding Biological Body Fluids Bos taurus Bronchoalveolar Lavage Cattle Cells Cigarette smoke-induced emphysema Cutaneous Defect Development Differentiation Antigens Disease EMSA Elastases Electrophoretic Mobility Shift Assay Epithelial Cells Epithelium Event Family Functional disorder Gene Expression Goals Healed Human IRAK1 gene Immune response In Vitro Infection Inflammation Inflammatory Inflammatory Response Injury Interferon Activation Interferon Type II Interferons Knock-out Knockout Mice LTA gene Lead Leukocytes Ligation Lipopolysaccharides Location Macrophage Activation Mass Spectrum Analysis Mediating Mediator of activation protein Microarray Analysis Mitogen-Activated Protein Kinases Modeling Molecular Mus Mycobacterium tuberculosis Myelogenous Names Neutrophil Activation Outcome Pancreatic Elastase Pathway interactions Peptides Peptidoglycan Phosphotransferases Physiological Principal Investigator Property Protease Inhibitor Protein Overexpression Protein Tyrosine Kinase Proteins Puncture procedure Reaction Recombinants Regulation Resolution Role STAT protein Sepsis Syndrome Septic Shock Serine Protease Serum Signal Transduction Site Source Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Surface TNF gene Testing Time Tissues Toll-like receptors Transgenes Transgenic Mice Trichloroacetic Acid Tumor Necrosis Factor-Beta Work Wound Healing Yeasts antileukoprotease base fetal healing homologous recombination human SLPI protein human disease in vivo insight interleukin-1 receptor-associated kinase leukocyte activation macrophage microbial mutant neutralizing antibody neutrophil novel novel strategies novel therapeutics prevent programs receptor research study response yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): Secretory leukocyte protease inhibitor (SLPI) and proepithelin (PEPI) were originally discovered as two unrelated secreted products of epithelial cells. SLPI is a small 12-kDa leukocyte protease inhibitor, while PEPI is best known as the precursor for epithelins (EPIs), a group of 6-kDa peptides with unknown functions that are found in diverse tissues and body fluids. Leukocytes, especially macrophages, are also rich sources of SLPI and PEPI. Expression of both proteins is upregulated in macrophages by microbial products such as lipopolysaccharide (LPS). We have identified PEPI as a SLPI interacting protein. We also discovered that PEPI and EPIs exert opposing biological activities. EPIs promote whereas PEPI downregulates inflammatory reactions. Binding of PEPI by SLPI prevents its conversion to EPIs. Both SLPI and PEPI block TNF-triggered neutrophil activation. SLPI also suppresses the macrophage response to LPS. Thus, SLPI and PEPI appear to be a pair of host-derived anti-inflammatory mediators that serve to prevent excess innate immune responses. The underlying mechanisms for the anti-inflammatory actions of SLPI and PEPI are poorly understood. The goal of this project is to further explore the mechanisms of the novel anti-inflammatory actions of SLPI and PEPI. We will focus on: (1) characterizing the role of PEPI/EPIs in the inflammatory responses of leukocytes; (2) understanding the molecular basis by which SLPI and PEPI affect macrophage function; and (3) testing the role of SLPI and PEPI in three in vivo inflammation models (cutaneous wounding, smoke-induced emphysema and septic shock induced by cecal-ligation and puncture) using PEPI and SLPI knock out mice and SLPI transgenic mice. Elucidating how SLPI and PEPI interfere with specific steps in LPS signaling may contribute important insights to the pathophysiology of inflammation-related diseases including septic shock and to the development of novel therapeutic strategies.

描述（由申请人提供）：分泌性白细胞蛋白酶抑制剂（SLPI）和上皮素原（PEPI）最初被发现是两种无关的上皮细胞分泌产物。SLPI是一种小的12-kDa白细胞蛋白酶抑制剂，而PEPI最为人所知的是上皮蛋白（EPI）的前体，这是一组在不同组织和体液中发现的功能未知的6-kDa肽。白细胞，特别是巨噬细胞，也是SLPI和PEPI的丰富来源。这两种蛋白质的表达在巨噬细胞中被微生物产物如脂多糖（LPS）上调。我们已经确定PEPI作为SLPI相互作用蛋白。我们还发现，PEPI和EPI发挥相反的生物活性。EPI促进而PEPI下调炎症反应。SLPI与PEPI的结合阻止其转化为EPI。SLPI和PEPI均阻断TNF触发的中性粒细胞活化。SLPI还抑制巨噬细胞对LPS的反应。因此，SLPI和PEPI似乎是一对宿主来源的抗炎介质，其用于防止过度的先天免疫应答。SLPI和PEPI的抗炎作用的潜在机制知之甚少。本课题的目的是进一步探讨SLPI和PEPI新的抗炎作用机制。我们将重点关注：（1）表征PEPI/EPI在白细胞炎症反应中的作用;（2）理解SLPI和PEPI影响巨噬细胞功能的分子基础;和（3）使用PEPI和SLPI敲除小鼠和SLPI转基因小鼠测试SLPI和PEPI在三种体内炎症模型（皮肤创伤、烟雾诱导的肺气肿和盲肠结扎和穿刺诱导的败血性休克）中的作用。阐明SLPI和PEPI如何干扰LPS信号传导中的特定步骤，可能有助于对炎症相关疾病（包括感染性休克）的病理生理学以及新治疗策略的开发的重要见解。