IL-6 induced by double-stranded RNA augments allergic inflammation via suppression of Foxp3+ T-cell/IL-10 axis.

Activation of innate immunity against viruses in the respiratory tracts affects the development of asthma. Most respiratory viruses generate double-stranded (ds)RNA during their replication. We recently showed that a low-dose administration of polyinosinic polycytidylic acid (poly IC), a mimetic of viral dsRNA, during allergen sensitization augments airway eosinophilia and hyperresponsiveness in mice via enhanced production of IL-13 from T cells. However, a phenotype of asthma under severer load of dsRNA remains unknown. d-galactosamine (d-GalN) is known as a strong sensitizer of poly IC. Mice were treated with poly IC plus d-GalN during allergen sensitization. A sublethal dose of poly IC/d-GalN augmented airway eosinophilia and CD4(+) T-cell accumulation in the lungs but not airway hyperresponsiveness. The augmented inflammation was associated with decreased IL-10 in the bronchoalveolar lavage fluid and decreased Foxp3(+) regulatory T cells in the lungs. Serum IL-6 was prominently higher in the mice treated with poly IC/d-GalN than in that with poly IC alone or d-GalN alone. Poly IC/d-GalN did not affect IL-17-producing T cells in the lungs. Poly IC/d-GalN failed to augment airway eosinophilia after anti-IL-10 receptor monoclonal antibody treatment during allergen challenge. Finally, anti-IL-6 receptor monoclonal antibody treatment before poly IC/d-GalN completely prevented the decrease of IL-10 and Foxp3(+) regulatory T cells and the augmentation of airway inflammation. These results indicate that enhanced production of IL-6 by poly IC/d-GalN induces the augmentation of allergic inflammation via suppression of Foxp3(+) regulatory T-cell/IL-10 axis. IL-6 may be a target for preventing asthma augmentation related to severe virus infection.