Rhinovirus Stimulation of Macrophage Signaling /Mediator

鼻病毒刺激巨噬细胞信号/介质

• 批准号: 7151330
• 负责人: PAUL JOHN BERTICS
• 金额: $ 17.18万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7151330
• 关键词: IP 10 protein; asthma; biological signal transduction; cAMP response element binding protein; cooperative study; human subject; interferon gamma; interleukin 13; interleukin 4; leukocyte activation /transformation; macrophage; mitogen activated protein kinase; monocyte chemoattractant protein 1; nuclear factor kappa beta; pathologic process; patient oriented research; respiratory infections; rhinovirus; transcription factor; tumor necrosis factor alpha

Macrophages are important for rhinovirus (RV)-induced exacerbation of asthma, but little is known about how macrophage activation status affects RV-intiated signaling events. Macrophage activation is a heterogeneous process wherein, depending on the stimuli, different classes of activated cells are generated that exhibit diverse immunological functions. One agent modulating macrophage function is the "classical" activator interferon-gamma (IFN-gamma). Conversely, alternatively-activated macrophages can be induced by IL-4 or IL-13. These different activation states result in the liberation of distinct profiles of mediators, with alternatively-activated cells exhibiting a reduced antimicrobial capacity. Because IL-4/IL-13 are important in asthma and can also promote alternatively-activated macrophage phenotypes, and given the contribution of IFN-gamma to virus-induced exacerbation of asthma, we postulate that the interaction of these diverse priming agents leads to a range of macrophage phenotypes that affect the resolution of infection and thus airflow obstruction and symptoms of asthma. Our initial studies reveal that RV challenge of airway macrophages leads to the release of pro-inflammatory factors (TNF-alpha, IP-10, MCP-1) and that airway macrophages from asthmatic patients exhibit an elaboration of mediators that is characteristic of alternatively-activated cells. Our studies have also shown that macrophage exposure to RV activates transcription factors (NF-KB, CREB and STAT1) and MAP kinases (Jun kinases and p38) that regulate gene expression and cytokine production. The overall hypothesis of this project is that macrophages from asthmatic subjects are directed towards alternatively-activated phenotypes, and upon interaction with RV, release cytokines/chemokines that lead to asthma exacerbation. Thus, the following aims are proposed: (1) Determine whether macrophages from asthmatic patients are directed towards alternatively-activated phenotypes (characterized by attenuated release of proinflammatory cytokines (TNFalpha, IFNalpha) and chemokines (MCP-1, IP-10) but enhanced production of IL-10). (2) Test whether the altered cytokine responses of macrophages from asthmatic patients is reflected by alterations in the kinetics/ intensity of signaling via MAPK, NF-kappa, GREB and STAT1. (3) Ascertain whether normal human blood monocyte-derived macrophages can be directed towards classically-activated or alternatively-activated phenotypes by factors (IL-4, IFN-gamma) relevant to RV-induced exacerbation of asthma.

巨噬细胞对鼻病毒（RV）诱导的哮喘加重很重要，但对其知之甚少