Rhinovirus Stimulation of Macrophage Signaling /Mediator

巨噬细胞在鼻病毒（RV）诱导的哮喘急性发作中起重要作用，但对巨噬细胞的作用知之甚少。 巨噬细胞活化状态如何影响RV引发的信号传导事件。巨噬细胞活化是一种 异质过程，其中，取决于刺激，产生不同类别的活化细胞 表现出不同的免疫功能。调节巨噬细胞功能的一种药剂是“经典的” 激活剂干扰素-γ（IFN-γ）。相反，IL-4可以诱导交替激活的巨噬细胞 或IL-13。这些不同的激活状态导致释放不同的介体， 交替活化的细胞表现出降低的抗微生物能力。因为IL-4/IL-13在 哮喘，也可以促进替代激活的巨噬细胞表型，并考虑到贡献 IFN-γ与病毒诱导的哮喘急性发作之间的关系，我们推测这些不同的激发的相互作用 因子导致一系列巨噬细胞表型，这些表型影响感染的消退，从而影响气流 阻塞和哮喘症状。我们的初步研究表明，呼吸道巨噬细胞的RV挑战， 导致促炎因子（TNF-α、IP-10、MCP-1）的释放， 哮喘患者表现出具有交替激活细胞特征的介质的精细化。 我们的研究还表明，巨噬细胞暴露于RV激活转录因子（NF-κ B，CREB 和STAT 1）和MAP激酶（Jun激酶和p38），其调节基因表达和细胞因子产生。 该项目的总体假设是，哮喘受试者的巨噬细胞被导向 交替活化的表型，并在与RV相互作用后，释放细胞因子/趋化因子， 哮喘恶化。因此，提出以下目的：（1）确定巨噬细胞是否来自 哮喘患者针对交替激活表型（特征在于减弱的 促炎细胞因子（TNF α、IFN α）和趋化因子（MCP-1、IP-10）的释放，但增加了 IL-10）。(2)测试哮喘患者巨噬细胞的细胞因子反应是否改变， 通过MAPK、NF-κ、GREB和STAT 1信号传导的动力学/强度的改变反映。 (3)确定正常人血单核细胞衍生的巨噬细胞是否可被定向于 通过与RV诱导相关的因子（IL-4，IFN-γ）经典激活或交替激活表型 哮喘恶化。

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.