College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Republic of Korea.
Cell Death Dis. 2013 May 23;4(5):e640. doi: 10.1038/cddis.2013.166.
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.
细胞因子和淋巴细胞的激活对于肿瘤生长至关重要。我们研究了白细胞介素（IL）-32β 的过表达是否会改变其他细胞因子水平并激活细胞毒性淋巴细胞，从而改变肿瘤生长。在此，IL-32β 在过表达 IL-32β 的转基因小鼠（IL-32β 小鼠）中抑制 B16 黑色素瘤的生长，并下调抗凋亡蛋白（bcl-2、IAP 和 XIAP）和细胞生长调节蛋白（Ki-67 抗原（Ki-67）和增殖细胞核抗原（PCNA））的表达，但上调促凋亡蛋白（bax、cleaved caspase-3 和 cleaved caspase-9）的表达。IL-32β 还抑制裸鼠接种过表达 IL-32β 的 SW620 结肠或 PC3 前列腺癌细胞后结肠和前列腺肿瘤的生长。IL-32β 的强制表达也抑制了培养的结肠和前列腺癌细胞的生长，而这些抑制作用被 IL-32 小干扰 RNA（siRNA）所消除。IL-10 水平升高，但 IL-1β、IL-6 和肿瘤坏死因子-α（TNF-α）水平在 IL-32β 小鼠和裸鼠的肿瘤组织和脾脏中降低。在 IL-32β 小鼠和接种过表达 IL-32β 的癌细胞的裸鼠中，肿瘤组织、脾脏和血液中的细胞毒性 T（CD8（+））和自然杀伤（NK）细胞数量显著增加。IL-32β 小鼠和接种过表达 IL-32β 的癌细胞的裸鼠的肿瘤组织以及培养的过表达 IL-32β 的癌细胞中，组成型激活的 NF-κB 和 STAT3 水平降低。这些发现表明，IL-32β 通过增加细胞毒性淋巴细胞的数量，并通过改变肿瘤组织中的细胞因子水平使 NF-κB 和 STAT3 途径失活，从而抑制肿瘤生长。
