RESUMO
BACKGROUND: Asthma and other Th2 inflammatory conditions have been associated with increased susceptibility to viral infections. The mechanisms by which Th2 cytokines can influence immune responses to infections are largely unknown. METHODS: We measured the effects of Th2 cytokines (IL-4 and IL-13) on bronchial epithelial cell innate immune antiviral responses by assessing interferon (IFN-ß and IFN-λ1) induction following rhinovirus (RV)-16 infection. We also investigated the modulatory effects of Th2 cytokines on Toll-like receptor 3 (TLR3), interferon-responsive factor 3 (IRF3) and nuclear factor (NF)-kB, that is key molecules and transcription factors involved in the rhinovirus-induced interferon production and inflammatory cascade. Pharmacological and redox modulation of these pathways was also assessed. RESULTS: Th2 cytokines impaired RV-16-induced interferon production, increased rhinovirus replication and impaired TLR3 expression in bronchial epithelial cells. These results were replicated in vivo: we found increased IL-4 mRNA levels in nasal epithelial cells from nasal brushing of atopic rhinitis patients and a parallel reduction in TLR3 expression and increased RV-16 replication compared to nonatopic subjects. Mechanistically, Th2 cytokines impaired RV-16-induced activation of IRF3, but had no effects on RV-16-induced NF-kB activation in bronchial epithelial cell cultures. N-acetylcysteine and phosphoinositide 3-kinase (PI3K) inhibitor restored the inhibitory effects of Th2 cytokines over RV-16-induced activation of IRF3. CONCLUSIONS: IL-4 and IL-13, through inhibition of TLR3 expression and signalling (IRF3), impair immune response to RV-16 infection. These data suggest that Th2 conditions increase susceptibility to infections and identify pharmacological approaches with potential to restore impaired immune response in these conditions.
Assuntos
Citocinas/metabolismo , Imunidade Inata/imunologia , Rhinovirus/imunologia , Receptor 3 Toll-Like/metabolismo , Asma/imunologia , Asma/metabolismo , Brônquios/citologia , Células Cultivadas , Citocinas/imunologia , Suscetibilidade a Doenças , Ensaio de Imunoadsorção Enzimática , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Humanos , Interleucina-13/imunologia , Interleucina-13/metabolismo , Interleucina-4/imunologia , Interleucina-4/metabolismo , NF-kappa B/imunologia , NF-kappa B/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Células Th2/imunologia , Células Th2/metabolismo , Receptor 3 Toll-Like/imunologiaRESUMO
Respiratory viral infections are recognized as the most frequent cause of asthma and chronic obstructive pulmonary disease (COPD) exacerbations with rhinovirus (i.e. the virus of the common cold) being the most frequent identified virus. The recent development of human experimental models of rhinovirus-induced asthma and COPD exacerbations represent innovative tools with the potential to increase our understanding in this field. Moreover this models will provide the opportunity to test, in a carefully controlled setting, novel pharmacological compounds. In this review we will provide an overview of the role of viral infections in asthma and COPD exacerbations and in particular we will summarize the inflammatory and immunological mechanisms that can pave the way to exacerbation following respiratory viral infection in these patients.
