C-EBPß mediates in cigarette/IL-17A-induced bronchial epithelial-mesenchymal transition in COPD mice.

BACKGROUND: Cigarettes smoking and IL-17A contribute to chronic obstructive pulmonary disease (COPD), and have synergistical effect on bronchial epithelial cell proliferation. CCAAT/enhancer-binding protein ß (C-EBPß) could be induced by IL-17A and is up-regulated in COPD. We explored the effect of cigarettes and IL-17 on bronchial epithelial-mesenchymal transition (EMT) in COPD mice and potential mechanism involved with C-EBPß in this study. METHODS: COPD model was established with mice by exposing to cigarettes. E-Cadherin, Vimentin, IL-17A and C-EBPß distributions were detected in lung tissues. Primary bronchial epithelial cells were separated from health mice and cocultured with cigarette smoke extract (CSE) or/and IL-17A. E-Cadherin, Vimentin and IL-17 receptor (IL-17R) expressions in vitro were assessed. When C-EBPß were silenced by siRNA in cells, E-Cadherin, Vimentin and C-EBPß expressions were detected. RESULTS: E-Cadherin distribution was less and Vimentin distribution was more in bronchus of COPD mice than controls. IL-17A and C-EBPß expressions were higher in lung tissues of COPD mice than controls. In vitro, C-EBPß protein expression was highest in CSE + IL-17A group, followed by CSE and IL-17A groups. E-cadherin expression in vitro was lowest and Vimentin expression was highest in CSE + IL-17A group, followed by CSE or IL-17A group. Those could be inhibited by C-EBPß silenced. CONCLUSIONS: C-EBPß mediates in cigarette/IL-17A-induced bronchial EMT in COPD mice. Our findings contribute to a better understanding on the progress from COPD to lung cancers, which will provide novel avenues in preventing tumorigenesis of airway in the context of cigarette smoking.

Rationally Designed Strigolactone Analogs as Antagonists of the D14 Receptor.

Strigolactones (SLs) are plant hormones that inhibit shoot branching and act as signals in communications with symbiotic fungi and parasitic weeds in the rhizosphere. SL signaling is mediated by DWARF14 (D14), which is an α/ß-hydrolase that cleaves SLs into an ABC tricyclic lactone and a butenolide group (i.e. D-ring). This cleavage reaction (hydrolysis and dissociation) is important for inducing the interaction between D14 and its target proteins, including D3 and D53. In this study, a hydrolysis-resistant SL analog was predicted to inhibit the activation of the D14 receptor, thereby disrupting the SL signaling pathway. To test this prediction, carba-SL compounds, in which the ether oxygen of the D-ring or the phenol ether oxygen of the SL agonist (GR24 or 4-bromo debranone) was replaced with a methylene group, were synthesized as novel D14 antagonists. Subsequent biochemical and physiological studies indicated that carba-SLs blocked the interaction between D14 and D53 by inhibiting D14 hydrolytic activity. They also suppressed the SL-induced inhibition of rice tiller outgrowths. Additionally, carba-SLs antagonized the SL response in a Striga parasitic weed species. Structural analyses revealed that the D-ring of 7'-carba-4BD was hydrolyzed by D14 but did not dissociate from the 4BD skeleton. Thus, 7'-carba-4BD functioned as an antagonist rather than an agonist. Thus, the hydrolysis of the D-ring of SLs may be insufficient for activating the receptor. This study provides data relevant to designing SL receptor antagonists.