IL-4 promotes airway eosinophilia by suppressing IFN-gamma production: defining a novel role for IFN-gamma in the regulation of allergic airway inflammation.
Airway eosinophilia in asthma is dependent on cytokines secreted by Th2 cells, including IL-5 and IL-4. In these studies we investigated why the absence of IL-4 led to a reduction in airway, but not lung tissue, eosinophils. Using adoptively transferred, in vitro-generated TCR-transgenic Th2 cells deficient in IL-4, we show that this effect is independent of IL-5 and Th2 cell generation. Airway eosinophilia was no longer inhibited when IL-4(-/-) Th2 cells were transferred into IFN-gammaR(-/-) mice, indicating that IFN-gamma was responsible for reducing airway eosinophils in the absence of IL-4. Intranasal administration of IFN-gamma to mice after IL-4(+/+) Th2 cell transfer also caused a reduction in airway, but not lung parenchymal, eosinophils. These studies show that IL-4 indirectly promotes airway eosinophilia by suppressing the production of IFN-gamma. IFN-gamma reduces airway eosinophils by engaging its receptor on hemopoietic cells, possibly the eosinophil itself. These studies capitalize on the complex counterregulatory effects of Th1 and Th2 cytokines in vivo and clarify how IL-4 influences lung eosinophilia. We define a new regulatory role for IFN-gamma, demonstrating that eosinophilic inflammation is differentially regulated at distinct sites within the respiratory tract.
Cohn
L
L
Sections of Pulmonary and Critical Care Medicine and Immunobiology, Department of Dermatology and Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA. lauren.cohn@yale.edu
Herrick
C
C
Niu
N
N
Homer
R
R
Bottomly
K
K
D000279:Administration, Cutaneous; D000281:Administration, Intranasal; D019264:Adoptive Transfer; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D016026:Bone Marrow Transplantation; D001980:Bronchi / Q000473:pathology*; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D004804:Eosinophils / Q000276:immunology / Q000473:pathology; D005260:Female; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D018793:Interleukin-13 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015848:Interleukin-5 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D011657:Pulmonary Eosinophilia / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D017471:Receptors, Interferon / Q000502:physiology; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D000096743:Interferon gamma Receptor
D007371:Interferon-gamma; D018793:Interleukin-13; D015847:Interleukin-4; D015848:Interleukin-5; D010047:Ovalbumin; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor