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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI070503-04
Application #
7919290
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
4
Fiscal Year
2009
Total Cost
$213,773
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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