Development of resistance to tumour necrosis factor (TNF alpha) in KYM-1 cells involves both TNF receptors.
In this study, we investigated the type of TNF receptor expressed by the human rhabdomyosarcoma cell line KYM-1 and related TNF-sensitive sublines and showed that the majority (> 90%) of TNF receptors were type II (p75) receptors with only a relatively small number (< 10%) of type I (p55) receptors. Selection with TNF alpha led to the isolation of KYM-1 related TNF-resistant cell lines of which three cloned lines showed a near to total loss of type II TNF receptors. To investigate further the role of each type of TNF receptor in the regulation of TNF-mediated cytotoxicity and the development of TNF resistance, we used receptor-specific antibodies and antisera, able to compete with ligand binding to the respective receptor molecules, but representing efficient agonists via crosslinking of receptors. We found that in KYM-1 and related TNF-sensitive sublines both type I and type II TNF receptors can be functional on their own, as selective cross-linking of each receptor subset lead to cytolysis. However, investigation of three TNF-resistant KYM-1 related cell lines by selective receptor stimulation via cross-linking indicated different mechanisms underlied the development of TNF-resistant for each receptor type. Our data indicate that resistance to TNF-mediated cytotoxicity in KYM-1 related cell lines can be developed both by a selective loss of type II receptor expression and the selective loss of type I receptor function without reduction in type I receptor numbers.
Meager
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A
Division of Immunobiology, National Institute for Biological Standards and Control, South Mimms, Hertfordshire, UK.
Sampson
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LE
Grell
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M
Scheurich
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P
D000911:Antibodies, Monoclonal / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D004351:Drug Resistance; D006801:Humans; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors* / Q000145:classification / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha