International Journal of COPD (Oct 2021)
GSK-3β Inhibitors Attenuate the PM2.5-Induced Inflammatory Response in Bronchial Epithelial Cells
Abstract
Weifeng Zou,1 Dong Ye,2 Sha Liu,3 Jinxing Hu,1 Tao Zhu,1 Fang He,4 Pixin Ran5 1State Key Laboratory of Respiratory Disease, Guangzhou Chest Hospital, Guangzhou, Guangdong, People’s Republic of China; 2State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 3The Second Hospital, University of South China, Hengyang, Hunan, People’s Republic of China; 4School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 5State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of ChinaCorrespondence: Pixin RanState Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Road, Yuexiu District, Guangzhou, Guangdong, 510120, People’s Republic of ChinaTel +86 13922765811Email [email protected] and Purpose: PM2.5-associated airway inflammation has recently been recognized as pivotal to the development of COPD. Aberrant glycogen synthase kinase (GSK)-3β signaling is linked to the inflammatory response. Therefore, we investigated the effects of GSK-3β inhibitors on the PM2.5-induced inflammatory response in bronchial epithelial cells.Methods: The production of phosphorylated GSK-3β (p-GSK-3β) was analyzed by immunohistochemistry with PM2.5-induced mice. HBECs were treated with various inhibitors targeting GSK-3β or JNK before PM2.5 stimulation. The production of GSK-3β signaling was analyzed by Western blotting. Inflammatory cytokine production was detected by qRT–PCR and ELISA.Results: PM2.5 exposure caused lung inflammation, upregulated serum concentrations of HMGB1 and IL-6, decreased IL-10 expression, and significantly attenuated p-GSK-3β production in mice. HBECs exposed to PM2.5 showed significantly reduced p-GSK-3β production, an increased ratio of p-JNK/JNK, increased NF-κB activation and IκB degradation, and upregulated the inflammatory cytokines HMGB1 and IL-6. Intervention with GSK-3β inhibitors TDZD-8 and SB216763 significantly suppressed PM2.5-induced outcomes. Moreover, the JNK inhibitor SP600125 also reduced the level of NF-κB phosphorylation induced by PM2.5. The differences in the levels of inflammation-related cytokines in the TDZD-8 groups were greater than those in the SB216763 groups.Conclusion: Inhibition of GSK-3β weakens the PM2.5-induced inflammatory response by regulating the JNK/NF-κB signaling pathway in bronchial epithelial cells.Keywords: PM2.5, COPD, GSK-3β, inflammatory response, HBECs
