In the context of allergic immune responses, activation of STAT6 is pivotal for Th2-mediated
IgE production and development of airway
inflammation and hyperreactivity. We analyzed whether gene silencing of STAT6 expression by RNA interference was able to suppress
allergen-induced immune and airway responses. Knockdown effectiveness of three different STAT6
siRNA molecules was analyzed in murine and human cell cultures. The most potent
siRNA was used for further testing in a murine model of
allergen-induced airway
inflammation and airway hyperreactivity (AHR). BALB/c mice were sensitized with
OVA/alum twice i.p. (days 1 and 14), and challenged via the airways with
allergen (days 28-30). Intranasal application of STAT6
siRNA before and during airway
allergen challenges reduced levels of infiltrating cells, especially of eosinophils, in the bronchoalveolar lavage fluid, compared with GFP
siRNA-treated sensitized and challenged controls.
Allergen-induced alterations in lung tissues (goblet cell
hyperplasia, peribronchial
inflammation with eosinophils and CD4 T cells) were significantly reduced after STAT6
siRNA treatment. Associated with decreased
inflammation was a significant inhibition of the development of
allergen-induced in vivo AHR after STAT6
siRNA treatment, compared with GFP
siRNA-treated sensitized and challenged controls. Importantly,
mRNA and
protein expression levels of
IL-4 and
IL-13 in lung tissues of STAT6-siRNA treated mice were significantly diminished compared with sensitized and challenged controls. These data show that targeting the key
transcription factor STAT6 by
siRNA effectively blocks the development of cardinal features of allergic airway disease, like
allergen-induced airway
inflammation and AHR. It may thus be considered as putative approach for treatment of allergic airway diseases such as
asthma.