IL-13-Induced Airway Hyperreactivity During Respiratory Syncytial Virus Infection Is STAT6 Dependent

Abstract

Airway damage and hyperreactivity induced during respiratory syncytial virus (RSV) infection can have a prolonged effect in infants and young children. These infections can alter the long-term function of the lung and may lead to severe asthma-like responses. In these studies, the role of IL-13 in inducing and maintaining a prolonged airway hyperreactivity response was examined using a mouse model of primary RSV infection. Using this model, there was evidence of significant airway epithelial cell damage and sloughing, along with mucus production. The airway hyperreactivity response was significantly increased by 8 days postinfection, peaked during days 10–12, and began to resolve by day 14. When the local production of Th1- and Th2-associated cytokines was examined, there was a significant increase, primarily in IL-13, as the viral response progressed. Treatment of RSV-infected mice with anti-IL-13 substantially inhibited airway hyperreactivity. Anti-IL-4 treatment had no effect on the RSV-induced responses. Interestingly, when IL-13 was neutralized, an early increase in IL-12 production was observed within the lungs, as was a significantly lower level of viral Ags, suggesting that IL-13 may be regulating an important antiviral pathway. The examination of RSV-induced airway hyperreactivity in STAT6−/− mice demonstrated a significant attenuation of the response, similar to the anti-IL-13 treatment. In addition, STAT6−/− mice had a significant alteration of mucus-producing cells in the airway. Altogether, these studies suggest that a primary factor leading to chronic RSV-induced airway dysfunction may be the inappropriate production of IL-13.

Critical Role for IL-13 in the Development of Allergen-Induced Airway Hyperreactivity

“…Similarly, Grunig et al (8) demonstrated that administration of either rIL-13 or rIL-4 to rag 1-deficient mice induced AHR, and the effects of these cytokines were mediated through an IL-4 receptor ␣-chaindependent pathway. These studies, demonstrating overlapping or complementary roles for IL-4 and IL-13 in the induction of AHR, are consistent with those using STAT6-deficient mice, which lack IL-4 and IL-13 signaling pathways and which do not develop AHR (19,20).…”

Modulation of mucus production by interleukin‐13 receptor α2 in the human airway epithelium

“…We also showed that the number of PAS-positive cells, goblet cells and STAT6 is well known to be a critical transcriptional factor for IL-13 and IL-4 signaling [29,30]. A previous report [11] suggested that IL-13 induces the expression of IL-13Rα 2 in bronchial epithelial cells, which was STAT6-dependent.…”

CD8+ T cell contributions to allergen induced pulmonary inflammation and airway hyperreactivity

“…It has already been shown that CD8 + T cells are necessary to cause airway hyperresponsiveness during respiratory syncytial virus infection (RSV) [40]. It has also been shown that IL-13 is produced during the response to RSV, and that blocking IL-13 causes a reduction in AHR induced upon infection [41]. Thus, it may be that CD8 + T cells play the primary role in viral exacerbation of asthma.…”