IL-23 / Il-17 and Lung Host Defense

IL-23 / IL-17 和肺宿主防御

基本信息

批准号：
7534377
负责人：
JAY K KOLLS
金额：
$ 39.24万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-10 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7534377
关键词：
Alveolar Macrophages Antigen-Presenting Cells Bacterial Pneumonia Biological Assay Bone Marrow C57BL/6 Mouse CD8B1 gene CXC Chemokines Calcium Cells Chemotaxis Clara cell-specific protein Clinical Coculture Techniques Collaborations Data Dendritic Cells Deposition Epithelial Cells Experimental Models Family member Fire - disasters Granulocyte Colony-Stimulating Factor Heating Host Defense Host Defense Mechanism IL-23 p19 In Vitro Infection Interleukin-12 Interleukin-17 Klebsiella pneumonia bacterium Knowledge Laboratories Life Lung Lymphocyte Lymphoid Tissue Marrow Mediating Modeling Mouse Strains Mus Myelogenous Neutrophil Infiltration Organism Patients Pneumonia Population Production Respiratory Burst Series Signal Transduction T-Lymphocyte TLR4 gene Testing Tin Tissues Universities cytokine human CXCL2 protein improved in vivo interleukin-23 killings macrophage macrophage inflammatory protein 2 neutrophil novel promoter receptor reconstitution research study respiratory response toll-like receptor 4

项目摘要

DESCRIPTION (provided by applicant): Bacterial pneumonia is an important clinical problem and host defense mechanisms against pneumonia are not fully understood. Preliminary data from our laboratory using a murine model of Klebsiella pneumoniae infection has shown that bacterial deposition in the lung results in the release of the T-cell derived cytokines IL-17A and IL-17F, both of which can mediate neutrophil recruitment into the lung. Moreover, we have shown that signaling through the IL-17 receptor is critical for optimal granulocyte-colony stimulating factor (G-CSF) and both Gro-alpha and macrophage inflammatory protein 2 (MIP-2) production in the lung which are critical for granulopoeisis and neutrophil chemotaxis respectively in this model. Furthermore, preliminary data using both in vitro bone marrow derived dendritic cells (DC) and T-cell co-cultures as well as in our experimental model of pneumoniae in vivo has demonstrated that host release of these lymphocyte-derived IL-17 family members is dependent on recognition of the organism by Toll-like receptor 4 (presumably on both alveolar macrophages and lung dendritic cells) and the subsequent production of IL-23 (a novel heterodimeric cytokine composed of a unique p19 subunit and the p40 subunit of IL-12) by these cell populations which signal to T-cell to produce IL-17. This data allows us to propose an experimental hypothesis that both TLR4 and IL-23 are required for the production of IL-17A and IL-17F in the lung and that IL-17R signaling by lung parenchymal cells is critical for host defense against Klebsiella pneumoniae. We will test this hypothesis with the following Specific Aims: 1. Our hypothesis predicts that TLR4 on lung DCs and alveolar macrophages is critical for pulmonary production of IL-23 and IL-17 in response to experimental K. pneumoniae infection. 2. Our hypothesis predicts that IL-23 is required for the production of IL-17A and IL-17F, G-CSF and optimal CXC chemokine production and subsequent neutrophil recruitment in response to experimental K. pneumoniae infection. 3. Our hypothesis predicts that IL-17R signaling by lung parenchymal cells is required for production of G-CSF and optimal CXC chemokine production and subsequent neutrophil recruitment in response to experimental K. pneumoniae infection.

描述（由申请人提供）：细菌性肺炎是一个重要的临床问题，宿主针对肺炎的防御机制尚未完全了解。我们实验室使用肺炎克雷伯菌感染的小鼠模型获得的初步数据表明，肺部的细菌沉积导致 T 细胞衍生的细胞因子 IL-17A 和 IL-17F 的释放，这两种细胞因子都可以介导中性粒细胞招募到肺部。此外，我们已经表明，通过 IL-17 受体的信号传导对于最佳粒细胞集落刺激因子 (G-CSF) 以及肺部 Gro-α 和巨噬细胞炎症蛋白 2 (MIP-2) 的产生至关重要，而这对于肺部的最佳粒细胞集落刺激因子 (G-CSF) 和巨噬细胞炎症蛋白 2 (MIP-2) 的产生至关重要。该模型中分别存在粒细胞生成和中性粒细胞趋化作用。此外，使用体外骨髓衍生的树突状细胞 (DC) 和 T 细胞共培养物以及我们的体内肺炎实验模型的初步数据表明，这些淋巴细胞衍生的 IL-17 家族成员的宿主释放是依赖于 Toll 样受体 4（可能在肺泡巨噬细胞和肺树突细胞上）对生物体的识别以及随后产生的 IL-23（一种由独特的 p19 亚基和IL-12 的 p40 亚基）由这些细胞群向 T 细胞发出信号以产生 IL-17。这些数据使我们能够提出一个实验假设，即 TLR4 和 IL-23 都是肺部产生 IL-17A 和 IL-17F 所必需的，并且肺实质细胞的 IL-17R 信号传导对于宿主防御肺炎克雷伯菌至关重要。我们将通过以下具体目标来检验这一假设： 1. 我们的假设预测肺 DC 和肺泡巨噬细胞上的 TLR4 对于响应实验性肺炎克雷伯菌感染而产生肺部 IL-23 和 IL-17 至关重要。 2. 我们的假设预测 IL-23 是产生 IL-17A 和 IL-17F、G-CSF 和最佳 CXC 趋化因子产生以及随后响应实验性肺炎克雷伯菌感染而招募中性粒细胞所必需的。 3. 我们的假设预测，肺实质细胞的 IL-17R 信号传导对于 G-CSF 的产生和最佳 CXC 趋化因子的产生以及随后响应实验性肺炎克雷伯菌感染的中性粒细胞募集是必需的。