Antitumor activity of IL-32β through the activation of lymphocytes, and the inactivation of NF-κB and STAT3 signals

Cytokine and activation of lymphocytes are critical for tumor growth. We investigated whether interleukin (IL)-32 beta overexpression changes other cytokine levels and activates cytotoxic lymphocyte, and thus modify tumor growth. Herein, IL-32 beta inhibited B16 melanoma growth in IL-32 beta-overexpressing transgenic mice (IL-32 beta mice), and downregulated the expressions of anti-apoptotic proteins (bcl-2, IAP, and XIAP) and cell growth regulatory proteins (Ki-67 antigen (Ki-67) and proliferating cell nuclear antigen (PCNA)), but upregulated the expressions of pro-apoptotic proteins (bax, cleaved caspase-3, and cleaved caspase-9). IL-32 beta also inhibited colon and prostate tumor growth in athymic nude mice inoculated with IL-32 beta-transfected SW620 colon or PC3 prostate cancer cells. The forced expression of IL-32 beta also inhibited cell growth in cultured colon and prostate cancer cells, and these inhibitory effects were abolished by IL-32 small interfering RNA (siRNA). IL-10 levels were elevated, but IL-1 beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha) levels were reduced in the tumor tissues and spleens of IL-32 beta mice, and athymic nude mice. The number of cytotoxic T (CD8(+)) and natural killer (NK) cells in tumor tissues, spleen, and blood was significantly elevated in IL-32 beta mice and athymic nude mice inoculated with IL-32 beta-transfected cancer cells. Constituted activated NF-kappa B and STAT3 levels were reduced in the tumor tissues of IL-32 beta mice and athymic nude mice, as well as in IL-32 beta-transfected cultured cancer cells. These findings suggest that IL-32 beta inhibits tumor growth by increasing cytotoxic lymphocyte numbers, and by inactivating the NF-kappa B and STAT3 pathways through changing of cytokine levels in tumor tissues.