Zhao Xueqiang, Mohaupt Mariette, Jiang Jing, Liu Shubai, Li Bing, Qin Zhihai
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Cancer Res. 2007 May 1;67(9):4443-50. doi: 10.1158/0008-5472.CAN-07-0185.
Tumor necrosis factor (TNF) binds to two different receptors. Although most of its functions are attributed to TNF receptor 1 (TNFR1), the independent role of TNFR2 is still largely unknown. Using TNFR single or double knock-out mice, we show here that the expression of TNFR2 alone on host cells was sufficient to suppress the growth of TNF-secreting tumors in both immune competent and T/B lymphocyte-deficient severe combined immunodeficiency (SCID) mice. Histologic studies showed that TNF recruited, via TNFR2, large numbers of macrophages and efficiently inhibited angiogenesis in the tumor. In vitro, TNF activated TNFR1-deficient macrophages to produce nitric oxide (NO). Treatment of TNFR1 knock-out mice with L-NAME, a specific NO synthase inhibitor, almost completely eliminated TNF-induced angiostasis and tumor suppression. Moreover, L-NAME acted only during the first few days of tumor growth. Our results show for the first time that TNFR2 expressed on host innate immune cells is sufficient to mediate the antitumor effect of TNF, and NO is necessary for this process, possibly by inhibition of angiogenesis in the tumor.
肿瘤坏死因子（TNF）可与两种不同的受体结合。尽管其大部分功能归因于肿瘤坏死因子受体1（TNFR1），但TNFR2的独立作用在很大程度上仍不清楚。利用TNFR单敲除或双敲除小鼠，我们在此表明，宿主细胞上单独的TNFR2表达足以抑制免疫健全和T/B淋巴细胞缺陷的严重联合免疫缺陷（SCID）小鼠中分泌TNF的肿瘤的生长。组织学研究表明，TNF通过TNFR2募集大量巨噬细胞，并有效抑制肿瘤中的血管生成。在体外，TNF激活TNFR1缺陷的巨噬细胞产生一氧化氮（NO）。用特异性NO合酶抑制剂L-NAME处理TNFR1敲除小鼠，几乎完全消除了TNF诱导的血管生成抑制和肿瘤抑制作用。此外，L-NAME仅在肿瘤生长的最初几天起作用。我们的结果首次表明，宿主先天免疫细胞上表达的TNFR2足以介导TNF的抗肿瘤作用，而NO对于该过程是必需的，可能是通过抑制肿瘤中的血管生成。
