Interleukin-9 Inhibits Lung Metastasis of Melanoma through Stimulating Anti-Tumor M1 Macrophages

• Published in: Molecules and cells 2020, 43(5), , pp.479-490
• Main Authors: Park, Sang Min, Do-Thi, Van Anh, Lee, Jie-Oh, Lee, Hayyoung, Kim, Young Sang
• Format: Article
• Language: English
• Subjects: Animals; Cytokines - metabolism; Female; Humans; Interleukin-9 - metabolism; Lung Neoplasms - immunology; Lung Neoplasms - secondary; Lung Neoplasms - therapy; Macrophage Activation; Macrophages - immunology; Melanoma - immunology; Melanoma - pathology; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasms, Experimental - immunology; Neoplasms, Experimental - pathology; Th1 Cells - immunology; 생물학
• ISSN: 1016-8478; 0219-1032
• DOI: 10.14348/molcells.2020.0047

Interleukin-9 (IL-9) is well known for its role in allergic inflammation. For cancer, both pro- and anti-tumor effects of IL-9 were controversially reported, but the impact of IL-9 on tumor metastasis has not yet been clarified. In this study, IL-9 was expressed as a secretory form (sIL-9) and a membrane-bound form (mbIL-9) on B16F10 melanoma cells. The mbIL-9 was engineered as a chimeric protein with the transmembrane and cytoplasmic region of TNF-α. The effect of either mbIL-9 or sIL-9 expressing cells were analyzed on the metastasis capability of the cancer cells. After three weeks of tumor implantation into C57BL/6 mice through the tail vein, the number of tumor modules in lungs injected with IL-9 expressing B16F10 was 5-fold less than that of control groups. The percentages of CD4 T cells, CD8 T cells, NK cells, and M1 macrophages considerably increased in the lungs of the mice injected with IL-9 expressing cells. Among them, the M1 macrophage subset was the most significantly enhanced. Furthermore, peritoneal macrophages, which were stimulated with either sIL-9 or mbIL-9 expressing transfectant, exerted higher anti-tumor cytotoxicity compared with that of the mock control. The IL-9-stimulated peritoneal macrophages were highly polarized to M1 phenotype. Stimulation of RAW264.7 macrophages with sIL-9 or mbIL-9 expressing cells also significantly increased the cytotoxicity of those macrophages against wild-type B16F10 cells. These results clearly demonstrate that IL-9 can induce an anti-metastasis effect by enhancing the polarization and proliferation of M1 macrophages.