Abstract
Airway neutrophilia has been known correlated with asthma severity. Thrombin plays a crucial role in asthma. Thrombin can induce IL-8/CXCL8 expression, a potent chemoattractant for neutrophils, in lung epithelial cells. Doublecortin-like kinase 1 (DCLK1) is a protein kinase that has been identified as a tumor stem cell marker in colon and pancreatic cancer. Here we investigated the role of DCLK1 in thrombin-induced IL-8/CXCL8 expression in human lung epithelial cells. Thrombin-induced IL-8/CXCL8 release was attenuated by DCLK1 siRNA or LRKK2-IN-1 (DCLK1 inhibitor) in BEAS-2B and A549 cells. Moreover, thrombin-induced IL-8/CXCL8 luciferase activity was inhibited by DCLK1 siRNA in A549 cells. Treatment of the cells with thrombin caused a time-dependent increase in phosphorylation of DCLK1 at Ser30, and its phosphorylation was attenuated by U0126 (ERK inhibitor). Thrombin also activates RhoA and YAP Ser127 dephosphorylation which were inhibited by DCLK1 siRNA and LRRKN2-IN-1. YAP is activated following dephosphorylation of its Ser127 site and translocates to nucleus, combines with transcription factor p65 to bind to κB promoter region, increasing IL-8/CXCL8 transcription. Taken together, these results demonstrate the role of DCLK1 in mediating thrombin-induced IL-8/CXCL8 expression through DCLK1/RhoA/YAP signaling axis in human lung epithelial cells. Our findings indicate a possible therapeutic strategy for the treatment of thrombin-mediated IL-8/CXCL8 expression in neutrophilic asthma.
Footnotes
Cite this article as: European Respiratory Journal 2021; 58: Suppl. 65, PA2526.
This abstract was presented at the 2021 ERS International Congress, in session “Prediction of exacerbations in patients with COPD”.
This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).
- Copyright ©the authors 2021
