IL-37 mediates the antitumor activity in renal cell carcinoma

Interleukin (IL)-37 is a natural suppressor of innate inflammatory and immune responses. IL-37 plays an important role in renal function and antitumor activity. The aim of this study was to investigate the role of IL-37 in renal cell carcinoma (Rcc). Serum IL-37 levels in 120 Rcc patients and 50 healthy controls were measured by enzyme-linked immunosorbent assay (ELISA). The Rcc cell lines A498 and Caki-1 were cultured with 0-100 ng/mL of recombinant human IL-37 protein (rhIL-37). Cancer cells were transfected with or without pcDNA3.1-IL-6 to alter IL-6 expression. Cell migration, proliferation, and apoptosis were tested by wound-healing assay, MTT, and flow cytometry, respectively. Levels of IL-6, pSTAT3 Y705, Bcl-2, cyclin D1, and HIF-1α were detected by qRT-PCR, ELISA, or western blot. Additionally, therapeutic effect of rhIL-37 was also confirmed in SCID mice. The expression of IL-37 was decreased in Rcc patients and was negatively correlated with tumor progression. In vitro, IL-37 markedly inhibited the migration and proliferation, and promoted apoptosis in Rcc cells. Furthermore, the expressions of IL-6, pSTAT3 Y705, HIF-1α, Bcl-2, and cyclin D1 were decreased by IL-37. However, these effects were reversed by the transfection of pcDNA3.1-IL-6. In vivo, tumor growth and gene expressions of IL-6 and HIF-1α were suppressed by IL-37. In conclusion, IL-37 might serve as a novel tumor suppressor in Rcc and exert its antitumor activity through inhibiting IL-6/STAT3 signaling.