title: WNT/β-catenin signaling regulates cigarette smoke-induced airway inflammation via the PPARδ/p38 pathway.
abstract: The mechanisms of WNT/β-catenin signaling involved in airway inflammation of chronic obstructive pulmonary disease (COPD) remain unknown, although recent observations have suggested an important contribution of the pathway in pulmonary parenchymal tissue repair and airway epithelium differentiation. We investigated the role of WNT/β-catenin signaling in cigarette smoke (CS)-related airway inflammation using patient lung tissues, human bronchial epithelial cells (16HBECs), and mouse models. Reduced activity of WNT/β-catenin signaling was observed in the airway epithelium of smokers with or without COPD. The mRNA expression of WNT transcription factor TCF4 negatively correlated with the pack year. The mRNA levels of WNT receptor FZD4 negatively correlated with the mRNA levels of IL-1β. CS exposure decreased the activity of WNT/β-catenin signaling in both 16HBECs and mice. In vitro studies demonstrated the upregulation of inflammatory cytokines TNF-α and IL-1β secretion induced by CS extract (CSE) could be attenuated by β-catenin activator SB216763 and be exacerbated by β-catenin small-interfering RNA (siRNA), respectively. Furthermore, the decrease in the expression of peroxisome proliferator-activated receptor (PPARδ) induced by CSE stimulation could be rescued by SB216763. SB216763 also attenuated the upregulation of phosphorylated p38 mitogen-activated protein kinase (MAPK) stimulated by CSE. Both PPARδ agonist and p38 MAPK inhibitor could suppress the TNF-α and IL-1β release induced by CSE treatment. In addition, PPARδ activation could abolish β-catenin siRNA-mediated aggravation of phosphorylated p38 MAPK in response to CSE. Finally, SB216763 treatment significantly ameliorated peribronchial inflammatory cell infiltration, leukocyte influx, and the release of TNF-α and IL-1β in the bronchoalveolar lavage fluid of CS-exposed mice. Taken together, our findings indicate that the reduced activity of WNT/β-catenin signaling induced by CS may promote inflammatory cytokine production in airway epithelium and have an essential role in airway inflammation in COPD by PPARδ/p38 MAPK pathway.
authors: Division of Pulmonary Diseases, Department of Respiratory Medicine, State Key Laboratory of Biotherapy of China, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors: Lingli
authors: L
authors: Guo
authors: Division of Pulmonary Diseases, Department of Respiratory Medicine, State Key Laboratory of Biotherapy of China, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors: Tao
authors: T
authors: Wang
authors: Division of Pulmonary Diseases, Department of Respiratory Medicine, State Key Laboratory of Biotherapy of China, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors: Yanqiu
authors: Y
authors: Wu
authors: Department of Biological Science, College of Life Science, Sichuan University, Chengdu, China.
authors: Zhicheng
authors: Z
authors: Yuan
authors: Division of Pulmonary Diseases, Department of Respiratory Medicine, State Key Laboratory of Biotherapy of China, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors: Jiajia
authors: J
authors: Dong
authors: Division of Pulmonary Diseases, Department of Respiratory Medicine, State Key Laboratory of Biotherapy of China, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors: Xiao'ou
authors: X
authors: Li
authors: Division of Pulmonary Diseases, Department of Respiratory Medicine, State Key Laboratory of Biotherapy of China, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors: Jing
authors: J
authors: An
authors: Division of Pulmonary Diseases, Department of Respiratory Medicine, State Key Laboratory of Biotherapy of China, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors: Zenglin
authors: Z
authors: Liao
authors: Division of Pulmonary Diseases, Department of Respiratory Medicine, State Key Laboratory of Biotherapy of China, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors: Xue
authors: X
authors: Zhang
authors: Division of Pulmonary Diseases, Department of Respiratory Medicine, State Key Laboratory of Biotherapy of China, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors: Dan
authors: D
authors: Xu
authors: Division of Pulmonary Diseases, Department of Respiratory Medicine, State Key Laboratory of Biotherapy of China, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors: Fu-Qiang
authors: FQ
authors: Wen
mesh_terms: D000368:Aged; D000818:Animals; D002460:Cell Line; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D047494:PPAR delta / Q000378:metabolism*; D011014:Pneumonia / Q000139:chemically induced*; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D047494:PPAR delta; D012906:Smoke; D051153:Wnt Proteins; D051176:beta Catenin; D048051:p38 Mitogen-Activated Protein Kinases