Effects of Arkadia on airway remodeling through enhancing TGF-beta signaling in allergic rats.
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.
Li
Xiao-Zhao
XZ
Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, China.
Feng
Jun-Tao
JT
Hu
Cheng-Ping
CP
Chen
Ze-Qi
ZQ
Gu
Qi-Hua
QH
Nie
Hua-Ping
HP
D000818:Animals; D001249:Asthma / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000473:pathology*; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D051906:Smad7 Protein / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; C525545:Ski protein, rat; C511209:Skil_v1 protein, rat; D051906:Smad7 Protein; C497808:Smad7 protein, rat; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C526200:Smurf2 protein, rat; C550853:Rnf111 protein, rat; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625843:Tgfbr1 protein, rat