Interleukin-1β Promotes Epithelial-Derived Alveolar Elastogenesis via αvβ6 Integrin-Dependent TGF-β Activation.
OBJECTIVE
IL-1β creates persistent pulmonary inflammation accompanied by elevated transforming growth factor β (TGF-β levels and is associated with abnormal elastogenesis, which is observed in bronchopulmonary dysplasia (BPD). Although progress has been made in this field, the mechanisms underlying this process remain only partially understood.


METHODS
We assessed aberrant elastin localization-associated signaling in mouse pups exposed to 85% O2 treated with either IL-1Ra or 1D11, using morphometric analyses, quantitative RT-PCR, immunostaining, and ELISA. We also evaluated the derivation of elastin-producing cells using dual marker tracking. The regulatory mechanisms of IL-1β were investigated in vitro in lung epithelial and mesenchymal cells.


RESULTS
Elevated levels of IL-1β, αvβ6 and TGF-β1 were each associated with aberrant elastin production in O2-exposed lungs. IL-1Ra abolished TGF-β1 activation and αvβ6 upregulation, which occurred as a result of exposure to hyperoxia, whereas 1D11 had no discernible effect on the expression of either αvβ6 or IL-1β even following O2-exposure, suggesting that IL-1β was initially induced. Additionally, double staining revealed the presence of epithelium-derived elastin-producing cells, which was confirmed via in vitro IL-1β stress-induced epithelial-mesenchymal transformation (EMT) morphological and molecular marker changes, which may explain the altered lung elastin deposition and defective septation observed in BPD.


CONCLUSIONS
These data support the hypothesis that IL-1β was initially induced by hyperoxia; αvβ6 subsequently interacted with and activated TGF-β1, acting as an epithelial/mesenchymal signaling molecule that contributed to excessive alveolar elastogenesis, the primary pathological feature of BPD.
Department of Neonatology, Children's Hospital of Chongqing Medical University, Chongqing, China.
Jiarong
J
Wang
Lei
L
Bao
Benli
B
Yu
Zhaoyun
Z
Liu
Wenli
W
Han
Chun
C
Deng
Chunbao
C
Guo
D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation; D004549:Elastin / Q000378:metabolism* / Q000648:ultrastructure; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018496:Hyperoxia / Q000235:genetics / Q000473:pathology; D016023:Integrins / Q000378:metabolism*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009024:Morphogenesis; D010641:Phenotype; D011650:Pulmonary Alveoli / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D015398:Signal Transduction / Q000235:genetics; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D000951:Antigens, Neoplasm; D016023:Integrins; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C073878:integrin alphavbeta6; D004549:Elastin