The roles of dipeptidyl peptidase-4 and its inhibitors in the regulation of airway epithelial-mesenchymal transition

Abstract

Objective: Dipeptidyl peptidase 4 (DPP4), also known as CD26, is a transmembrane glycoprotein with peptidase activity expressed on epithelial cells and some immune cells. It also occurs as a soluble form. Studies have revealed that the expression level of lymphocyte sCD26/sDPP4 was elevated in the asthmatic patients. Airway remodeling increases in asthma severity and these structural changes include, amongst others, the loss of epithelial integrity because of cell shedding, goblet cell hyperplasia, destruction of ciliated cells, and EMT. So we try to find whether sCD26/sDPP4 has a role in pathological/dysregulated transition from bronchial epithelial cells into fibroblasts cells in response to TGFβ1 exposure in vitro. Therefore, our purpose in the present work was to identify the role of sCD26/sDPP4 in airway EMT regulation. Methods: The EMT cell model was established based on human 16HBE cells. The effects of sCD26/sDPP4 and its inhibitors on airway EMT and that of sCD26/sDPP4 on Th17/IL-17 and its role in airway EMT were investigated in vitro. Results: The mRNA and protein level of E-Cadherin decreased after the treatment of TGF-β1 in 16HBE cells, while α-SMA was up-regulated. The level of E-Cadherin was significantly down-regulated after the sCD26/sDPP4 stimulation, and that of α-SMA was dramatically elevated. DPP4 inhibitors promoted the level of E-cadherin and inhibited that of α-SMA. Additionally, in the DPP4-treated IL-17 cells group, E-Cadherin was markedly down-regulated at the mRNA and protein level, while α-SMA was reversely up-regulated. Conclusion: The TGF-β1-induced EMT of human bronchial epithelial cells could be promoted by sCD26/sDPP4. The suppression of EMT in human bronchial epithelial cells was achieved by DPP4 inhibitor, and the TGF-β1-mediated EMT of human airway cells was promoted by the synergy of IL-17 and sCD26/sDPP4 in vitro.

Keywords:

• sCD26/sDPP4
• asthma
• Th17/IL-17
• EMT
• airway remodeling

Disclosure statement

The authors declare that they have no competing interests.

Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 81560007 and No. 81760009).

Authors’ contributions

Libing Ma and Jingyi Sun designed the study. Jingyi Sun, Minyan Lu, Qilu Pan, Daofu Li and Shaojie Zheng performed the experiment. Shuyuan Chu performed statistical analyses. Jingyi Sun wrote the manuscript. All authors contributed to the revision and approved the final manuscript. The supporting data can be accessed from Libing Ma and Jingyi Sun.