Tumor necrosis factor receptor 2-mediated tumor suppression is nitric oxide dependent and involves angiostasis.
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.
Zhao
Xueqiang
X
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Mohaupt
Mariette
M
Jiang
Jing
J
Liu
Shubai
S
Li
Bing
B
Qin
Zhihai
Z
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D005260:Female; D008262:Macrophage Activation / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000276:immunology; D008297:Male; D012515:Mast-Cell Sarcoma / Q000098:blood supply / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000276:immunology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*; D010954:Plasmacytoma / Q000098:blood supply / Q000235:genetics / Q000276:immunology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide