Abstract
IL-33 played an important role in inflammatory diseases as evidenced by their high levels of expression in diseased tissues. Previous studies showed that IL-33/ST2L signal transduction pathway participated in epithelial-mesenchymal transition (EMT) of A549 cells. Cytokine IL-1β can increase the expression of MMPs by activating NF-kB. The excessive or inappropriate expression of MMP-9 may randomly and non-selectively destroy the extracellular matrix. TIMP-1 (tissue inhibitor of MMP-9) effects on ebb and flow of ECM by inhibiting activation of MMP-9. Therefore, IL-33 may take part in the process of pulmonary fibrosis by regulating expressions of MMP-9 and TIMP-1. To explore the acting mechanism of IL-33 in pulmonary fibrosis, proliferation of the human embryonic lung fibroblasts and expressions of related signal molecules was analyzed in vitro. We cultured HELF cells and stimulated HELF with rhIL-33 at different time points (24, 48, 72 h) and different concentrations respectively. The expression of the receptor ST2L was analyzed by RT-PCR and the proliferative rate of HELF was tested by MTT. The expressions of collagen IV, MMP-9, TIMP-1, and critical signal transducer TRAF-6 and NF-kappaB were tested by Western blotting. The rhIL-33 can promote proliferation of HELF and the concentration of 10 ng/ml was most significant at 72 h (P < 0.05). Hence, this experiment chose 10 ng/ml as stimulated concentration at following experiments. The expressions of collagen IV, MMP-9, TIMP-1, TRAF-6, and NF-kappaB increased and then reduced in protein levels at different time points (0, 6, 12, 24, 48, 72 h) (P < 0.05). IL-33 participates in the production of profibrotic cytokines and formation of mesenchymal substances in early inflammatory responses of pulmonary fibrosis. IL-33 can regulate deposition of ECM and promote the process of pulmonary fibrosis by inducing the imbalance between MMP-9 and TIMP-1.
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We thank the Jiangsu University lab for the support in performing the experiments.
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LW participated in the design of the study, carried out experiment and data collection, performed data analysis, drafted the manuscript, and revised it critically for intellectual content. ZL participated in the design of the study, performed data analysis, helped to draft the manuscript, and revised it critically for intellectual content. JZ, PY, ZY, XL, JZ, and MW participated in the design of the study. All authors read and approved the final manuscript.
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The study was performed at Beijing Chao-Yang Hospital, Beijing, and Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province.
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Wu, L., Luo, Z., Zheng, J. et al. IL-33 Can Promote the Process of Pulmonary Fibrosis by Inducing the Imbalance Between MMP-9 and TIMP-1. Inflammation 41, 878–885 (2018). https://doi.org/10.1007/s10753-018-0742-6
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DOI: https://doi.org/10.1007/s10753-018-0742-6