Pulmonary fibrosis (PF) is a lethal fibrotic lung disease. The role of lncRNAs in multiple diseases has been confirmed, but the role and mechanism of lncRNA zinc finger antisense 1 (ZFAS1) in the progression of PF need to be elucidated further. Here, we found that lncRNA ZFAS1 was upregulated in bleomycin (BLM)-induced PF rats lung tissues and transforming growth factor-β1 (TGF-β1)-treated HFL1 cells, and positively correlated with the expression of solute carrier family 38 member 1 (SLC38A1), which is an important regulator of lipid peroxidation. Moreover, knockdown of lncRNA ZFAS1 significantly alleviated TGF-β1-induced fibroblast activation, inflammation and lipid peroxidation. In vivo experiments showed that inhibition of lncRNA ZFAS1 abolished BLM-induced lipid peroxidation and PF development. Mechanistically, silencing of lncRNA ZFAS1 attenuated ferroptosis and PF progression by lncRNA ZFAS1 acting as a competing endogenous RNA (ceRNA) and sponging miR-150-5p to downregulate SLC38A1 expression. Collectively, our studies demonstrated the role of the lncRNA ZFAS1/miR-150-5p/SLC38A1 axis in the progression of PF, and may provide a new biomarker for the treatment of PF patients.
AbstractsBackgroundIL-27 is a multifunctional cytokine that has both pro-inflammatory and anti-inflammatory functions. Although IL-27 has been shown to potently inhibit lung fibrosis, the detailed mechanism of IL-27 in this process is poorly understood. Epithelial–mesenchymal transition (EMT) is one of the key mechanisms involved in pulmonary fibrosis. We assessed the effects of IL-27 on TGF-β1-induced EMT in alveolar epithelial cells.MethodsA549 cells (a human AEC cell line) were incubated with TGF-β1, IL-27, or both TGF-β1 and IL-27, and changes in E-cadherin, β-catenin, vimentin and a-SMA levels were measured using real-time PCR, western blotting and fluorescence microscopy. The related proteins in the JAK/STAT and TGF-β/Smad signalling pathways were examined by western blot.ResultsIL-27 increased the expression of epithelial phenotypic markers, including E-cadherin and β-catenin, and inhibited mesenchymal phenotypic markers, including vimentin and a-SMA in A549 cells. Moreover, TGF-β1-induced EMT was attenuated by IL-27. Furthermore, we found that TGF-β1 activated the phosphorylation of JAK1, STAT1, STAT3, STAT5, Smad1, Smad3 and Smad5, and IL-27 partially inhibited these changes in this process. When cells were treated with the STAT3 specific inhibitor wp1006 and the Smad3 specific inhibitor SIS3, the inhibition of EMT by IL-27 was significantly strengthened.ConclusionOur results suggest that IL-27 attenuates epithelial–mesenchymal transition in alveolar epithelial cells in the absence or presence of TGF-β1 through the JAK/STAT and TGF-β/Smad signalling pathways.Electronic supplementary materialThe online version of this article (doi:10.1186/s12860-016-0084-x) contains supplementary material, which is available to authorized users.
BackgroundInterleukin-27 (IL-27) is a multifunctional cytokine with both pro-inflammatory and immunoregulatory functions. At present, the role of IL-27 in pulmonary fibrosis remains unknown.MethodsIn this study, we observed the expression of IL-27/IL-27R in a mouse model of bleomycin (BLM)-induced pulmonary fibrosis. We verified the role of IL-27 using hematoxylin and eosin as well as Masson’s staining methods and measuring the content of hydroxyproline as well as collagen I and III. We assessed the differentiation of T lymphocytes in the spleen and measured the concentration of cytokines in bronchoalveolar lavage fluid (BALF) and the expression level of relevant proteins in the JAK/STAT and TGF-ß/Smad signaling pathways in lung tissue.ResultsIncreased IL-27 expression in BLM-induced pulmonary fibrosis was noted. IL-27 treatment may alleviate pulmonary fibrosis and increase the survival of mice. IL-27 inhibited the development of CD4+ IL-17+, CD4+ IL-4+ T, and CD4+ Foxp3+ cells and the secretion of IL-17, IL-4, IL-6, and TGF-ß. IL-27 induced the production of CD4+ IL-10+ and CD4+ INF-γ+ T cells. IL-27 decreased the levels of phosphorylated STAT1, STAT3, STAT5, Smad1, and Smad3 but increased the level of SOCS3.ConclusionsThis study demonstrates that IL-27 potentially attenuates BLM-induced pulmonary fibrosis by regulating Th17 differentiation and cytokine secretion.
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