IL-18 Mediates Obstruction-Induced Renal Injury via TLR4 Signaling

IL-18 通过 TLR4 信号介导梗阻性肾损伤

基本信息

批准号：
8637983
负责人：
KIRSTAN K MELDRUM
金额：
$ 31.87万
依托单位：
SPECTRUM HEALTH HOSPITALS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8637983
关键词：
Adult Agonist Animal Model Anti-Inflammatory Agents Anti-inflammatory Apoptosis Apoptotic Binding Binding Sites Caspase-1 Cell Death Cells Child Chronic Chronic Kidney Failure Clinical Colitis Cytokine Inducible SH2-Containing Protein Data Deletion Mutagenesis Development Disease Elements Epithelial Epithelial Cells Extracellular Matrix Family Feedback Fibrosis Gene Expression Genes Genetic Transcription Human Hyperglycemia Immunologics In Vitro Infiltration Inflammation Mediators Inflammatory Injury Interferons Interleukin-1 Interleukin-18 Investigation Kidney Kidney Diseases Kidney Failure Liver Mediating Mediator of activation protein Mesenchymal Modeling Mus Obstruction Patients Process Production Property Recombinant Interleukin-18 Role STAT3 gene Signal Pathway Signal Transduction Small Interfering RNA Source TNF gene Testing Therapeutic Transcription Factor AP-1 Transplantation Tubular formation Ureteral obstruction Urinary tract cell injury clinically relevant cytokine in vivo inhibitor/antagonist insight interleukin-18 receptor macrophage mutant novel prevent promoter public health relevance receptor receptor expression response toll-like receptor 4 treatment strategy urinary

项目摘要

DESCRIPTION (provided by applicant): Obstruction of the upper urinary tract is a major clinical problem that results in progressive, and ultimately, irreversible renal insufficiency. The majority of obstructive renal injury is attributed to progressive tubulointerstitial fibrosis and renal tubular epithelial cell damage. Interleukin 18 (IL-18) is a recently discovered pro-inflammatory cytokine that is structurally and functionally related to the IL-1 family. In humans, urinary IL-18 levels have been shown to be a sensitive and early marker of renal tubular damage from ischemic and post-transplantation ATN17, 84. Recently, circulating IL-18 levels and renal IL-18 receptor (IL-18R) expression has been shown to be elevated in patients with chronic kidney disease18, 85, 86. We therefore sought to examine IL-18's role in obstruction-induced tubulointerstitial fibrosis. Our preliminary data suggests that IL-18 stimulates obstruction-induced renal fibrosis, epithelial mesenchymal transition (EMT), and apoptotic cell death without altering downstream TNF-1 or TGF-21 activity. IL-18 was further observed to stimulate an increase in toll like receptor 4 (TLR4) expression during renal obstruction in vivo and upon direct stimulation of tubular epithelial cells in vitro, and direct antagonism of TLR4 in vitro reduced markers of IL-18-induced tubular cell injury, while direct stimulation of TLR4 increased markers of IL-18-induced tubular cell injury. We therefore hypothesize that IL-18 is a critical mediator of tubulointerstitial fibrosis and tubular epithelial cell damage during obstruction, and further, that IL-18's injurious effect is mediated through increased TLR4 expression. We will investigate this hypothesis by inducing unilateral ureteral obstruction (UUO) in genetically altered mice or by direct stimulation of tubular epithelial cells in vitro, and examine IL-18's role in obstruction-induced fibrosis, EMT, and apoptosis. We will then evaluate IL-18-induced TLR4 expression and activity as a mechanism of renal fibrosis and tubular epithelial cell damage, and finally, will evaluate STAT3's role in downstream IL-18 and TLR-4 signal transduction during UUO and its contribution to obstruction-induced fibrosis, EMT, and apoptosis. These studies will help elucidate the important role of IL-18 in obstructive renal injury and may provide a clinically relevant therapeutic strategy for the treatment of obstructive renal injury.

描述（由申请人提供）：上尿路的阻塞是导致渐进性的主要临床问题，最终导致不可逆的肾功能不全。大多数阻塞性肾脏损伤归因于进行性肾小管间隙纤维化和肾小管上皮细胞损伤。白介素18（IL-18）是最近发现的促炎细胞因子，在结构和功能上与IL-1家族有关。在人类中，尿IL-18水平已被证明是缺血性和移植后ATN17，84的肾小管损伤的敏感和早期标志。阻塞引起的肾小管间隙纤维化。我们的初步数据表明，IL-18刺激阻塞诱导的肾纤维化，上皮间质转变（EMT）和凋亡细胞死亡，而不会改变下游TNF-1或TGF-21活性。进一步观察到IL-18，以刺激体内肾脏阻塞期间的受体4（TLR4）表达的增加，并在体外直接刺激肾小管上皮细胞时，直接抑制TLR4在体外拮抗IL-18诱导的管状细胞损伤的标记，而直接刺激了TLR4刺激的TLR4刺激性标记。因此，我们假设IL-18是梗阻期间肾小管间质纤维化和肾小管上皮细胞损伤的关键介体，此外，IL-18的伤害作用是通过TLR4表达增加而介导的。我们将通过在遗传改变的小鼠中诱导单侧输尿管障碍物（UUO）或直接刺激肾小管上皮细胞，并检查IL-18在梗阻诱导的纤维化，EMT和凋亡中的作用。然后，我们将评估IL-18诱导的TLR4表达和活性，作为肾纤维化和管状上皮细胞损伤的机制，最后，将评估Stat3在UUO期间UUO的下游IL-18和TLR-4信号转导的作用及其对阻塞诱导的纤维化的贡献，EMT和Apoptosis。这些研究将有助于阐明IL-18在阻塞性肾脏损伤中的重要作用，并可能为治疗阻塞性肾脏损伤提供临床相关的治疗策略。