Signal transducer and activator of transcription 6 (STAT6) expression in lung epithelial cells plays a central role in
asthma pathogenesis, with its activation driving the development of airway hyper-reactivity and local
inflammation. Therefore, inhibition of local STAT6 expression provides a rationale for therapeutic intervention in
bronchial asthma. Given the absence of specific inhibitory drugs, we tested the ability of small interfering RNAs (siRNAs) to target STAT6 gene expression through the molecular process of RNA interference (RNAi). At pico-molar concentrations, STAT6-specific siRNAs potently inhibited STAT6
mRNA expression in lung epithelial cells (50% inhibitory concentration range = 134-861 pm) without inducing cellular
interferon responses. Detectable
STAT6 protein expression was rapidly abolished within 48 hr of treatment (t(1/2) range = or < 12-37 hr) and this was unaffected by pretreatment with STAT6-activating
cytokines. Furthermore, STAT6 suppression by RNAi produced downstream functional inhibitory effects in that
interleukin (IL)-13- or IL-4-driven eotaxin
chemokine family [
chemokine (C-C motif) ligand 11 (CCL11), CCL24 and CCL26]
mRNA expression was markedly inhibited. Induction of detectable CCL26
protein synthesis was completely ablated by pretreating cells with STAT6-specific
siRNA. The therapeutic potential of this approach is further demonstrated by novel findings that cells pre-exposed to
IL-13 or
IL-4 and subsequently treated with STAT6-targeting
siRNA exhibited a rapid and significant attenuation of ongoing CCL26
protein expression, suggesting that chronic
asthma-associated
lung inflammation will be responsive to this approach.