Abstract
Cytokine and activation of lymphocytes are critical for tumor growth. We investigated whether interleukin (IL)-32β overexpression changes other cytokine levels and activates cytotoxic lymphocyte, and thus modify tumor growth. Herein, IL-32β inhibited B16 melanoma growth in IL-32β-overexpressing transgenic mice (IL-32β 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-32β also inhibited colon and prostate tumor growth in athymic nude mice inoculated with IL-32β-transfected SW620 colon or PC3 prostate cancer cells. The forced expression of IL-32β 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-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) levels were reduced in the tumor tissues and spleens of IL-32β 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-32β mice and athymic nude mice inoculated with IL-32β-transfected cancer cells. Constituted activated NF-κB and STAT3 levels were reduced in the tumor tissues of IL-32β mice and athymic nude mice, as well as in IL-32β-transfected cultured cancer cells. These findings suggest that IL-32β inhibits tumor growth by increasing cytotoxic lymphocyte numbers, and by inactivating the NF-κB and STAT3 pathways through changing of cytokine levels in tumor tissues.
Highlights
A vast diversity of cytokines, growth factors, and inflammatory mediators released from tumor-associated stromal cells may directly influence the behavior of tumor cells or indirectly influence them by inducing changes in growth signals or by activating cytotoxic lymphocytes.[2]
Fluorescenceactivated cell sorting (FACS) analysis showed that CD8 þ T and natural killer (NK) cell numbers and total B cell numbers in blood, spleen, and tumor tissues of IL-32b mice and IL-32bC, and IL-32bp nude mice were significantly higher than in nontransgenic mice and IL-32bv nude mice (Figures 4c and d). These findings suggest that the antitumor immunity of IL-32b is associated with promoting the infiltration of CD8 þ T cells and NK cells into tumor tissues, and increasing the numbers of these cells in immune tissues and blood
Confocal microscopy confirmed that the nuclear translocations of p65 and p-STAT3 were reduced by IL-32b in both colon and prostate cancer cells (Figure 5g right panel). These results suggest that IL-32b inactivated NF-kB and STAT3 in tumor tissues, which are associated with the antitumor activity of IL-32b
Summary
A vast diversity of cytokines, growth factors, and inflammatory mediators released from tumor-associated stromal cells may directly influence the behavior of tumor cells or indirectly influence them by inducing changes in growth signals or by activating cytotoxic lymphocytes.[2] Cytokines are known to be significantly involved in tumor development and progression.[3]. Cytokines can directly influence the retardation or promotion of tumor growth through the activation of lymphocytes.[26] the activation of NF-kB and/or STAT3 in tumor-associated stromal inflammatory and immune cells can indirectly influence tumor growth by affecting the tumorinhibiting activity of lymphocytes, or by increasing the number. Received 25.3.13; revised 15.4.13; accepted 16.4.13; Edited by Stephanou of tumor-inhibiting lymphocytes.[27,28] Taken together, interaction between tumors and immune cells either enhance or inhibit cancer development and/or progression, and changes of cytokines could affect the activation of lymphocytes, and the activation of NF-kB and STAT3 signals, which control tumor growth
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