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：
8250012
负责人：
KIRSTAN K MELDRUM
金额：
$ 31.36万
依托单位：
UNIVERSITY OF FLORIDA
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 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8250012
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. PUBLIC HEALTH RELEVANCE: Obstruction of the kidney is a major clinical problem in both children and adults that results in progressive and ultimately irreversible kidney damage. While increased expression of the inflammatory mediator, interleukin 18 (IL-18), has been demonstrated in a wide range of kidney diseases, the role of IL-18 in obstruction-induced kidney injury remains unknown. This investigation would provide novel insight into IL-18's signaling mechanisms and its role in the development of obstruction-induced kidney damage, and in turn, provide potentially clinically relevant therapeutic strategies to limit or prevent the kidney damage associated with obstruction.

描述（由申请人提供）：上尿路梗阻是一个主要的临床问题，导致进行性的、最终不可逆的肾功能不全。大多数梗阻性肾损伤归因于进行性肾小管间质纤维化和肾小管上皮细胞损伤。白介素 18 (IL-18) 是最近发现的一种促炎细胞因子，其结构和功能与 IL-1 家族相关。在人类中，尿 IL-18 水平已被证明是缺血性和移植后 ATN17 引起的肾小管损伤的敏感早期标志物，84。最近，循环 IL-18 水平和肾脏 IL-18 受体 (IL-18R)研究表明，慢性肾病患者的表达水平升高18,85,86。因此，我们试图研究 IL-18 在梗阻性肾小管间质纤维化中的作用。我们的初步数据表明，IL-18 会刺激梗阻诱导的肾纤维化、上皮间质转化 (EMT) 和细胞凋亡，而不会改变下游 TNF-1 或 TGF-21 的活性。进一步观察到 IL-18 在体内肾梗阻期间和体外直接刺激肾小管上皮细胞后刺激 Toll 样受体 4 (TLR4) 表达增加，并且体外直接拮抗 TLR4 减少了 IL-18 诱导的标记物肾小管细胞损伤，而直接刺激 TLR4 会增加 IL-18 诱导的肾小管细胞损伤的标志物。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质，并且进一步，IL-18 的有害作用是通过 TLR4 表达增加介导的。我们将通过在基因改造小鼠中诱导单侧输尿管梗阻 (UUO) 或在体外直接刺激肾小管上皮细胞来研究这一假设，并检查 IL-18 在梗阻诱导的纤维化、EMT 和细胞凋亡中的作用。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肾小管上皮细胞损伤的机制，最后，将评估 STAT3 在 UUO 期间下游 IL-18 和 TLR-4 信号转导中的作用及其对梗阻的贡献-诱导纤维化、EMT和细胞凋亡。这些研究将有助于阐明IL-18在梗阻性肾损伤中的重要作用，并可能为梗阻性肾损伤的治疗提供临床相关的治疗策略。公共卫生相关性：肾梗阻是儿童和成人的一个主要临床问题，会导致进行性且最终不可逆转的肾脏损害。虽然炎症介质白细胞介素 18 (IL-18) 的表达增加已在多种肾脏疾病中得到证实，但 IL-18 在梗阻性肾损伤中的作用仍不清楚。这项研究将为 IL-18 的信号传导机制及其在梗阻性肾损伤发展中的作用提供新的见解，进而提供潜在的临床相关治疗策略，以限制或预防与梗阻相关的肾损伤。