Department of Pathology, College of Korean Medicine, Dong-eui University, Busan, 47227, Republic of Korea.
Department of Biochemistry, College of Korean Medicine, Dong-eui University, Busan, 47227, Republic of Korea.
Biochem Biophys Res Commun. 2020 Jul 5;527(4):889-895. doi: 10.1016/j.bbrc.2020.04.160. Epub 2020 May 16.
Tumor-associated macrophages (TAMs) are closely related with poor prognosis of cancers. The current study investigated whether lupeol regulates TAMs by focusing on the recruitment and polarization of macrophages. We found that lupeol suppressed the recruitment of THP-1 macrophages (THP-1 cells differentiated into macrophages) towards H1299 lung carcinoma cells by inhibiting plasminogen activator inhibitor-1 (PAI-1) production from H1299 cells. The reduced migration of THP-1 macrophages by lupeol was recovered by adding recombinant human PAI-1 as a chemoattractant. Knockdown of PAI-1 or treatment of tiplaxtinin, a PAI-1 inhibitor, in H1299 cells abrogated the chemotaxis of macrophages. Furthermore, lupeol suppressed the interleukin (IL)-4- and IL-13-induced M2 macrophage polarization. The mRNA expression of M2 macrophage markers and the phosphorylation of signal transducer and activator of transcription 6 (STAT6) were commonly decreased by lupeol in RAW264.7 cells. In addition, lupeol-suppressed M2 macrophage polarization led to the reduced migration of Lewis lung carcinoma (LLC) cells. Taken together, our results suggest that lupeol attenuates PAI-1-mediated macrophage recruitment towards cancer cells and inhibits M2 macrophage polarization.
肿瘤相关巨噬细胞（TAMs）与癌症的预后不良密切相关。本研究通过关注巨噬细胞的募集和极化来研究是否羽扇醇通过抑制 H1299 细胞中纤溶酶原激活物抑制剂-1（PAI-1）的产生来调节 TAMs。我们发现，羽扇醇通过抑制 H1299 细胞中纤溶酶原激活物抑制剂-1（PAI-1）的产生来抑制 THP-1 巨噬细胞（THP-1 细胞分化为巨噬细胞）向 H1299 肺癌细胞的募集。添加重组人 PAI-1 作为趋化剂可恢复羽扇醇对 THP-1 巨噬细胞迁移的抑制作用。在 H1299 细胞中敲低 PAI-1 或用 PAI-1 抑制剂 tiplaxtinin 处理可消除巨噬细胞的趋化性。此外，羽扇醇抑制白细胞介素（IL）-4 和 IL-13 诱导的 M2 巨噬细胞极化。在 RAW264.7 细胞中，羽扇醇普遍降低了 M2 巨噬细胞标志物的 mRNA 表达和信号转导和转录激活因子 6（STAT6）的磷酸化。此外，羽扇醇抑制 M2 巨噬细胞极化导致 Lewis 肺癌（LLC）细胞迁移减少。综上所述，我们的研究结果表明，羽扇醇可减弱 PAI-1 介导的巨噬细胞向癌细胞的募集，并抑制 M2 巨噬细胞极化。
