Hematopoietic progenitor cells of transgenic mice with increased copper/zinc-superoxide dismutase activity are resistant to tumor necrosis factor

Autor: Carlson E, Sakashita A, Epstein Cj, Koeffler Hp
Rok vydání: 1994
Předmět:
Zdroj: Journal of Cellular Physiology. 160:233-238
ISSN: 1097-4652
0021-9541
DOI: 10.1002/jcp.1041600204
Popis: The mechanism of growth inhibition mediated by tumor necrosis factor (TNF) is unclear. Since recent data strongly suggested that generation of superoxide is a key step in cytotoxicity of TNF, we reasoned that cells expressing high levels of enzymes that degrade superoxide radicals would be resistant to TNF. Therefore, we examined the TNF-sensitivity of bone marrow progenitor cells of transgenic mice that expressed the gene for human copper zinc-superoxide dismutase (CuZn-SOD). The CuZn-SOD is a key enzyme in the metabolism of superoxide radicals. Heterozygous and homozygous transgenic mice had 3- and 5-fold increased levels of CuZn-SOD activity, respectively. Bone marrow cells of transgenic and nontransgenic mice were plated in soft gel culture with TNF (0.01–100 ng/ml). TNF inhibited myeloid colony formation supported by either granulocyte-macrophage colony-stimulating factor (GM-CSF) or G-CSF from nontransgenic mice in a dose-dependent manner. In contrast, the myeloid clonal growth of homozygote transgenic mice was not inhibited by TNF at concentrations up to 100 ng/ml. As expected, the effects of TNF on erythroid clonogenic cells, which do not produce superoxide, and the action of transforming growth factor-β on myeloid progenitor cells, were similar in both transgenic and nontransgenic mice. These results suggest that the mechanism of TNF-mediated growth inhibition of hematopoietic cells occurs through production of superoxide. © 1994 Wiley-Liss, Inc.
Databáze: OpenAIRE
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