Interleukin-37 suppresses hepatocellular carcinoma growth through inhibiting M2 polarization of tumor-associated macrophages.

Abstract Interleukin (IL)-37 has anti-tumor effects in hepatocellular carcinoma (HCC). Evidence shows that tumor-associated macrophages (TAMs) promote tumor progression. This study was designed to investigate the functional role of IL-37-mediated polarization of TAMs in HCC progression. HCC patient-derived TAMs were transfected with lentiviruses expressing IL-37 (LV-IL-37) and IL-37 siRNA and then the conditioned medium from TAMs were used to culture HCC cells (HepG2 and Huh-7). The phenotype of the macrophages was evaluated by detecting M1- or M2- type specific markers and cytokines. Cell proliferation, migration, and invasion were assessed. A tumor xenograft mouse model was generated with a subcutaneous injection of a mixture of HepG2 cells and TAMs/LV-IL-37. HCC patient-derived PBMCs showed M2 polarization and decreased IL-37 expression. Furthermore, IL-37 promoted TAMs polarization from M2 to M1 subtype through inhibiting the IL‐6/STAT3 signaling. Moreover, IL-6 upregulation by recombinant human IL-6 (rhIL-6) blocked the IL-37 overexpression-mediated inhibition of HCC cell proliferation, migration, and invasion. In addition, IL-37 overexpression in HCC patient-derived TAMs inhibited tumor growth in vivo. Collectively, IL-37 suppresses HCC growth through inhibiting M2 polarization of TAMs via regulating the IL-6/STAT3 pathway.