Allergic environment enhances airway epithelial pro-inflammatory responses to rhinovirus infection.

Airway epithelial cells (AEC) exhibit a pro-inflammatory phenotype in patients with allergic asthma. We examined the effect of an allergic cytokine environment on the response of AEC to rhinovirus, the most common trigger of acute exacerbations of asthma. Calu-3 cells, a well-differentiated human AEC line, were cultured with or without the T-helper type 2 cytokines IL-4 and IL-13, then stimulated with a toll-like receptor (TLR) 3 agonist (poly I:C, dsRNA) or a TLR7 agonist (imiquimod), or infected with rhinovirus 16. Expression of pro-inflammatory and anti-viral mediators, and of viral pattern-recognition molecules, was assessed using nCounter assays, quantitative real-time PCR, and protein immunoassays. Both dsRNA and imiquimod stimulated expression of mRNA for IL6 and IL8, while expression of several chemokines and anti-viral response genes was induced only by dsRNA. Conversely, expression of other cytokines and growth factors was induced only by imiquimod. Rhinovirus infection not only stimulated expression of the inflammation-related genes induced by dsRNA, but also the complement pathway gene CFB and the novel pro- inflammatory cytokine IL32. In the Th2 cytokine environment, several mediators exhibited significantly enhanced expression, while expression of interferons was either unchanged or enhanced. The allergic environment also increased expression of pattern recognition receptors and of ICAM1, the cell surface receptor for rhinovirus. We conclude that Th2 cytokines promote increased production of pro- inflammatory mediators by AEC following infection with rhinovirus. Increased viral entry or enhanced signaling via pattern recognition receptors could also contribute to the exaggerated inflammatory response to rhinovirus observed in allergic asthmatics.