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 cel ls, including IL-5 and IL-4, In these studies we investigated why the absen ce of IL-4 led to a reduction in airway, but not lung tissue, eosinophils. Using adoptively transferred, in vitro-generated TCR-transgenic Th2 cells d eficient in IL-4, we show that this effect is independent of IL-5 and Th2 c ell generation. Airway eosinophilia was no longer inhibited when IL-4(-/-) Th2 cells were transferred into IFN-gammaR(-/-) mice, indicating that IFN-g amma was responsible for reducing airvp ag 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, eosi nophils, These studies show that IL-4 indirectly promotes airway eosinophil ia by suppressing the production of IFN-gamma. IFN-gamma reduces airway eos inophils by engaging its receptor on hemopoietic cells, possibly the eosino phil itself, These studies capitalize on the complex counterregulatory effe cts of Th1 and Th2 cytokines in vivo and clarify how IL-4 influences lung e osinophilia, We define a new regulatory role for IFN-gamma, demonstrating t hat eosinophilic inflammation is differentially regulated at distinct sites within the respiratory tract.