Upregulation of
transforming growth factor-beta (
TGF-beta) signaling is interrelated with the development of
airway remodeling. In this study, we examined the role of two E3
ubiquitin ligases, Arkadia and Smurf2, which are critically required for
TGF-beta signaling in
airway remodeling. Rats were immunized with
ovalbumin (OVA) and then challenged with an OVA
aerosol. In in vitro experiments, normal human bronchial epithelial cells were stimulated with TGF-beta(1) with or without the preincubation of Arkadia/Smurf2
small interfering RNA (
siRNA) or
lactacystin (an inhibitor of proteasomal degradation). In the lungs of OVA-treated rats, a large number of inflammatory cells were present near the airways. An increased subepithelial
collagen deposition was associated with high expression levels of Smad7, SnoN and Ski mRNAs, Arkadia, Smurf2, and
TGF-beta type I receptor (TbetaRI), but low expression levels of Smad7, SnoN and Ski
proteins. Smad7, SnoN and Ski interacted with both Arkadia and Smurf2 while TbetaRI only interacted with Smurf2 but not with Arkadia. In in vitro experiments, the inhibitory effect of TGF-beta(1) on the expression of Smad7, SnoN and Ski was reversed by Arkadia
siRNA and
lactacystin, whereas the stimulatory effect of TGF-beta(1) on the expression of TbetaRI
protein and Smad7/SnoN/Ski mRNAs was not affected. In contrast, Smurf2
siRNA did not influence the effects of TGF-beta(1) on the expression of the above
proteins. Our results suggest that Arkadia may contribute to the pathogenesis of
airway remodeling through enhancing
TGF-beta signaling by inducing the reduction of Smad7, SnoN and Ski
proteins in OVA-sensitized and -challenged rats.