IL-23 / Il-17 and Lung Host Defense

IL-23 / IL-17 和肺宿主防御

• 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
• 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

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，对肺炎的宿主防御机制尚不完全了解。 我们实验室的初步数据使用肺炎的鼠模型的鼠模型表明，肺中的细菌沉积会导致T细胞衍生的细胞因子IL-17A和IL-17F的释放，这两种都可以介导嗜中性粒细胞递送到肺中。此外，我们已经表明，通过IL-17受体的信号传导对于最佳的粒细胞 - 固定刺激因子（G-CSF）以及GRO-ALPHA和巨噬细胞炎性蛋白2（MIP-2）的肺部产生至关重要，这对于该模型中的颗粒状磷脂和中性粒细胞化学至关重要。 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细胞）和随后的IL-23（由独特的p19亚基组成的新型异二聚体细胞因子和IL-12的p40亚基组成），这些细胞种群向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，即肺部产生IL-17A和IL-17F所必需的TLR4和IL-23，并且肺实质细胞的IL-17R信号传导对于针对克莱伯斯氏菌肺炎的宿主防御至关重要。 我们将以以下特定目的检验这一假设：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K.肺炎感染而对IL-23和IL-17的肺产生至关重要。 2。我们的假设预测，IL-23是生产IL-17A和IL-17F，G-CSF以及最佳CXC趋化因子产生以及随后响应实验性肺炎感染的中性粒细胞募集所必需的。 3。我们的假设预测，肺实质细胞的IL-17R信号转导G-CSF和最佳的CXC趋化因子的产生以及随后对实验性K.肺炎感染的嗜中性粒细胞募集需要的IL-17R信号。