Stemona alkaloids suppress the positive feedback loop between M2 polarization and fibroblast differentiation by inhibiting JAK2/STAT3 pathway in fibroblasts and CXCR4/PIK/AKT1 pathway in macrophages.
International Immunopharmacology(2019)
Abstract
This study aimed to investigate the interaction between macrophages and fibroblasts in pulmonary fibrosis and the effects of total alkaloids of Stemona tuberosa (STA, 9 alkaloids with relative content of 91.2%) on them. The culture medium of LPS- or IL-4-induced macrophages was used as conditioned medium (CM) to co-culture with fibroblasts to study the effect of macrophages on the differentiation of fibroblasts. Similarly,the CM of TGF-β1-induced fibroblasts was co-culture with macrophages to study the effect of fibroblasts on the polarization of macrophages. The results showed that the TGF-β1 level in IL-4-induced (M2) rather than LPS-induced (M1) macrophages was significantly high (p < 0.001), and the SDF-1 level in TGF-β1-induced fibroblasts (MF) was significantly high (p < 0.001). The expressions of α-SMA and Col-1 in M2-CM-induced fibroblasts and Arg-1 and CXCR4 in MF-CM-induced macrophages were significantly increased (p < 0.01). STA effectively decreased the expressions of α-SMA (p < 0.05, 0.01 at 10, 100 μg/mL), Col-1 (p < 0.05, 0.05, 0.01 at 1, 10, 100 μg/mL), Arg-1 (p < 0.01 at 1, 10, 100 μg/mL) and CXCR4 (p < 0.01, 0.001 at 10, 100 μg/mL), which were consistent with the experimental results in vivo. These results suggested that there was a positive feedback loop between M2 polarization and fibroblast differentiation in pulmonary fibrosis. Further studies showed that the transcription of sdf-1 gene in MF was initiated by JAK2/STAT3 pathway and the M2 polarization was promoted by SDF-1/CXCR4/PI3K/AKT1 pathway. STA blocked the feedback loop by suppressing JAK2/STAT3 pathway in fibroblasts and CXCR4-PI3K/AKT1 pathway in macrophages.
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Key words
Pulmonary fibrosis,Stemona tuberosa,Macrophage,TGF-β1,Fibroblast,SDF-1
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