Pathophysiological effects of human TNF‐alpha‐producing tumor xenografts in immunosuppressed mice
Tóm tắt
Groups of CBA mice immunosuppressed with antithymocyte serum (ATS) treatment were xeno‐transplanted with either HeLa human cervical carcinoma cells or genetically modified cells expressing the human tumor necrosis factor‐α (TNF) gene (All cells). Both cell lines were highly resistant to the cytotoxic effects of TNF. If 3 times 106 tumor cells were inoculated s.c. into female mice, HeLa cells grew progressively into large tumors and killed 74% of the recipients, while TNF‐expressing All cells caused fatal tumor growth only in 22% of the mice. 3times 106 or 1.5times 107 All cells produced progressive tumor growth and lethality in all male recipients. In sera of all the All‐cell‐transplanted mice, biologically active TNF was detected shortly (4.5 h) after tumor inoculation (6–39 U/ml), decreasing to below detection level in the circulation by day 3. In recipients of 15 million All cells, circulating TNF reappeared and reached high levels (12–1000 U/ml) 3 to 7 weeks later, when the animals bore large tumors (14–23 mm). Generally, such mice became cachectic, severely anemic, hypothermic, and soon died. On account of calcium mobilization from bones, their serum Ca levels were high. Electron microscopy revealed severe liver damage, but there were no signs of chronic arthritis. These results suggest that ATS‐treated mice xenotransplanted with TNF‐gene‐transfected All human tumor cells provide a new model for studying the pathophysiological and anti‐tumor effects of TNF.
Từ khóa
Tài liệu tham khảo
Aggarwal BB, 1996, Tumor necrosis factors: developments during the last decade., Eur Cytokine Netw, 7, 93
Bauss F., 1987, Tumor necrosis factor mediates endotoxic effects in mice., Infect Immun, 55, 1622, 10.1128/iai.55.7.1622-1625.1987
Bendtzen K., 1989, Possible role of IL‐1, TNF‐alpha and IL‐6 in insulin‐dependent diabetes mellitus and autoimmune thyroid disease., Lymphokine Res, 8, 335
Beutler B., 1992, The molecules and their emerging role in medicine
Derijk RH, 1994, Hypothermia to endotoxin involves the cytokine tumor necrosis factor and the neuropeptide vasopressin in rats., Am J Physiol, 266, R9
Georgopoulos S., 1996, Transmembrane TNF is sufficient to induce localized tissue toxicity and chronic inflammatory arthritis in transgenic mice., J Inflamm, 46, 86
Jánossy T., 1992, The effect of TNF producing tumor grafts in mice., Eur Cytokine Netw, 3, 195
Johnson RA, 1989, Chronic exposure to tumor necrosis factor in vivo preferentially inhibits erythropoiesis in nude mice., Blood, 74, 130, 10.1182/blood.V74.1.130.130
Ksontini R., 1998, Disparate roles for TNF‐alpha and Fas ligand in concanavalin A‐induced hepatitis., J Immunol, 160, 4082, 10.4049/jimmunol.160.8.4082
Leist M., 1994, Murine hepatocyte apoptosis induced in vitro and in vivo by TNF‐alpha requires transcriptional arrest, J Immunol, 153, 1778, 10.4049/jimmunol.153.4.1778
Moldawer LL, 1989, Cachectin/tumor necrosis factor‐alpha alters red blood cell kinetics and induces anemia in vivo., FASEB J, 3, 1637, 10.1096/fasebj.3.5.2784116
Pócsik É, 1995, Phosphorylation of the 26 kDa TNF precursor in monocytic cells and in transfected HeLa cells., J Inflamm, 54, 152
Tsutsui H., 1997, IL‐18 accounts for both TNF‐alpha‐ and Fas ligand‐mediated hepatotoxic pathways in endotoxin‐induced liver injury in mice., J Immunol, 159, 3961, 10.4049/jimmunol.159.8.3961