Role of local pulmonary IFN-gamma expression in murine allergic airway inflammation.
Generalized underrepresentation of IFN-gamma has been implicated in the development of allergic asthma. However, the role of local IFN-gamma in the lung during the development of this disease has not been completely elucidated. We studied the influence of local pulmonary IFN-gamma expression on the development of allergen-induced lung inflammation. To restrict our analysis to IFN-gamma expression in the lung and to exclude influences of systemic IFN-gamma production, we generated a transgenic mouse line with a targeted deletion of the IFN-gamma gene and constitutive, lung-specific IFN-gamma expression (Clara cell 10 [CC10]-IFN-gamma-tg-IFN-gamma-KO mice), and compared allergen-induced airway inflammation in these mice with that of wild-type and IFN-gamma- KO mice on the C57BL/6 background. Cytokine quantification in lungs of mice with allergic airway inflammation revealed that pulmonary IFN-gamma expression increased expression of IL-5 and IL-13. Consistent with this observation, eosinophilia in bronchoalveolar lavage of CC10-IFN-gamma-tg-IFN-gamma-KO mice was profoundly increased, indicating that this critical component of asthma is enhanced by local IFN-gamma expression. In contrast, airway hyperresponsiveness and anti-ovalbumin-IgE serum levels were reduced by local IFN-gamma expression. Together, our results demonstrate pleiotropic action of constitutive IFN-gamma expression in the lung, and question the therapeutic value of IFN-gamma in allergic asthma. Local expression of IFN-gamma in the lung increases markers of allergic airway inflammation, but decreases airway hyperresponsiveness in a murine model of allergic-asthma.
Department of Immunology, Max-Planck-Institute for Infection Biology, Campus Charité Mitte, Schumannstrasse 21/22, 10117 Berlin, Germany. koch@mpiib-berlin.mpg.de
Markus
M
Koch
Martin
M
Witzenrath
Christine
C
Reuter
Marion
M
Herma
Hartwig
H
Schütte
Norbert
N
Suttorp
Helen
H
Collins
Stefan H E
SH
Kaufmann
D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D015415:Biomarkers / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D004802:Eosinophilia / Q000276:immunology; D007073:Immunoglobulin E / Q000097:blood; D007249:Inflammation / Q000473:pathology; D007371:Interferon-gamma / Q000276:immunology*; D018793:Interleukin-13 / Q000096:biosynthesis / Q000276:immunology; D015848:Interleukin-5 / Q000096:biosynthesis / Q000276:immunology; D008168:Lung / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis
D015415:Biomarkers; D018793:Interleukin-13; D015848:Interleukin-5; D012333:RNA, Messenger; D007073:Immunoglobulin E; D007371:Interferon-gamma; D010047:Ovalbumin