The contribution of IFN-g to the development and activity of disease in asthma has been debated for many years. IFN-g has been shown to both inhibit and exacerbate allergic airway inflammation. The goal of this proposal is to clarify how IFN-g functions in the regulation of allergic airway inflammation. Allergic airway inflammation is driven by Th2 cells, through the production of IL-4 and IL-13. IFN-g inhibits Th2-induced pathways by effects on IL-4/IL-13 signaling and IFN-g has hundreds of other pro-inflammatory effects that, under certain conditions, increase airway inflammation. We show that IFN-g inhibits Th2-induced responses in the respiratory tract, including having striking effects on mucus, eosinophilia and Th2 cell number in the airways. IFN-g also controls airway chitinase activity, a recently characterized, pro-inflammatory Th2 effector pathway in asthma. We have defined circumstances in which IFN-g is pro-inflammatory and leads to extensive neutrophilia. Our hypotheses are 1) IFN-g inhibits Th2 cytokine-dependent inflammatory pathways in the respiratory tract. 2) Anti-inflammatory effects of IFN-g are most prominent when low IFN-g levels are present in the airways and when Th1 cells/IFN-g are administered in the setting of ongoing Th2 inflammation, IFN-g enhances inflammation and neutrophilia. 3) IFN-g stimulates a distinctive pattern of cellular and molecular pathways in the regulation of mucus, chitinase and eosinophilia.
The aims of this project are:
AIM I. Define the cellular and molecular mechanisms of IFN-g inhibition of Th2 effector functions in the respiratory tract.
AIM II. Determine the mechanism of IFN-g inhibition of eosinophilia and its relationship to the reciprocal induction of neutrophilia.
AIM III. Determine how IFN-g regulates the number of Th2 cells in the respiratory tract.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL064040-05
Application #
6926893
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Banks-Schlegel, Susan P
Project Start
2000-04-01
Project End
2010-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
5
Fiscal Year
2005
Total Cost
$408,750
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Mitchell, Charlotte; Provost, Karin; Niu, Naiqian et al. (2011) IFN-? acts on the airway epithelium to inhibit local and systemic pathology in allergic airway disease. J Immunol 187:3815-20
Niu, Naiqian; Le Goff, Marc K; Li, Fangyong et al. (2007) A novel pathway that regulates inflammatory disease in the respiratory tract. J Immunol 178:3846-55
Homer, Robert J; Zhu, Zhou; Cohn, Lauren et al. (2006) Differential expression of chitinases identify subsets of murine airway epithelial cells in allergic inflammation. Am J Physiol Lung Cell Mol Physiol 291:L502-11
Cohn, Lauren (2006) Mucus in chronic airway diseases: sorting out the sticky details. J Clin Invest 116:306-8
Cohn, Lauren; Whittaker, Laurie; Niu, Naiqian et al. (2002) Cytokine regulation of mucus production in a model of allergic asthma. Novartis Found Symp 248:201-13; discussion 213-20, 277-
Whittaker, Laurie; Niu, Naiqian; Temann, U-Angela et al. (2002) Interleukin-13 mediates a fundamental pathway for airway epithelial mucus induced by CD4 T cells and interleukin-9. Am J Respir Cell Mol Biol 27:593-602