In vivo disruption of TGF-beta signaling by Smad7 in airway epithelium alleviates allergic asthma but aggravates lung carcinogenesis in mouse.
BACKGROUND
TGF-beta has been postulated to play an important role in the maintenance of epithelial homeostasis and the development of epithelium-derived cancers. However, most of previous studies are mainly focused on the function of TGF-beta in immune cells to the development of allergic asthma and how TGF-beta signaling in airway epithelium itself in allergic inflammation is largely unknown. Furthermore, the in vivo TGF-beta function specifically in the airway epithelium during lung cancer development has been largely elusive.


RESULTS
To evaluate the in vivo contribution of TGF-beta signaling in lung epithelium to the development of allergic disease and lung cancer, we generated a transgenic mouse model with Smad7, an intracellular inhibitor of TGF-beta signaling, constitutively expressed in mouse airway Clara cells using a mouse CC10 promoter. The mice were subjected to the development of OVA-induced allergic asthma and urethane-induced lung cancer. The Smad7 transgenic animals significantly protected from OVA-induced asthma, with reduced airway inflammation, airway mucus production, extracellular matrix deposition, and production of OVA-specific IgE. Further analysis of cytokine profiles in lung homogenates revealed that the Th2 cytokines including IL-4, IL-5 and IL-13, as well as other cytokines including IL-17, IL-1, IL-6, IP10, G-CSF, and GM-CSF were significantly reduced in the transgenic mice upon OVA induction. In contrast, the Smad7 transgenic animals had an increased incidence of lung carcinogenesis when subjected to urethane treatment.


CONCLUSIONS
These studies, therefore, demonstrate for the first time the in vivo function of TGF-beta signaling specifically in airway epithelium during the development of allergic asthma and lung cancer.
Luo
Xiaolin
X
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Chinese Academy of Sciences, Shanghai, China.
Ding
Qiurong
Q
Wang
Min
M
Li
Zhigang
Z
Mao
Kairui
K
Sun
Bing
B
Pan
Yi
Y
Wang
Zhenzhen
Z
Zang
Ying Qin
YQ
Chen
Yan
Y
D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000209:etiology* / Q000628:therapy; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D015316:Genetic Therapy; D007249:Inflammation / Q000517:prevention & control; D008175:Lung Neoplasms / Q000139:chemically induced / Q000209:etiology* / Q000628:therapy; D051379:Mice; D008822:Mice, Transgenic; D010047:Ovalbumin; D020545:Respiratory Mucosa / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051906:Smad7 Protein / Q000235:genetics / Q000494:pharmacology*; D018418:Th2 Cells; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000502:physiology*; D014520:Urethane
D016207:Cytokines; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D016212:Transforming Growth Factor beta; D014520:Urethane; D010047:Ovalbumin
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