RESPONSES OF HUMAN GLIOBLASTOMA CELLS TO HUMAN NATURAL TUMOR-NECROSIS-FACTOR-ALPHA - SUSCEPTIBILITY, MECHANISM OF RESISTANCE AND CYTOKINE PRODUCTION STUDIES

Responses and susceptibility of 14 human glioblastoma cell lines to hu man natural tumor necrosis factor-alpha (TNF) were studied in vitro. S usceptibility of glioblastoma cells to TNF varied in experimental cond itions applied. Most of glioblastoma cell lines were resistant to cyto toxic activity of TNF in a MTT assay at concentrations below 16U/ml fo r 72 h exposure. However, TNF at higher dose, in prolonged exposure an d against low density of target cells was antiproliferative for certai n glioblastoma cultures. TNF exposure at 10U/ml for 48 h suppressed DN A synthesis in 9 of 14 glioblastoma cultures, but increased in 3 cultu res. In addition, colony forming assay showed anti-clonogenic activity of TNF in 5 of 6 glioblastoma cell lines tested. In spite of their lo w susceptibility to TNF, glioblastoma cells well responded to TNF stim ulation at low dose (10U/ml) for a short period in the absence of cell damage. Productions of Interleukin-6 (IL-6), IL-8-like activity, gran ulocyte-macrophage colony stimulating factor (GM-CSF), prostaglandin E 2 (PGE2) and manganous superoxide dismutase (Mn-SOD) were enhanced or induced by the low-dose TNF stimulation. Mn-SOD, a protein protective against oxidative cell damage, was well induced in time- and dose-depe ndent manner, however did not correlate with TNF resistance. Whereas t he levels of PGE2 in TNF-susceptible cell lines, H-4 and SF-188, were higher than those of other lines. In conclusion, most of glioblastoma cells are resistant to TNF cytotoxic effects, but highly responsive to TNF stimulation. Its effect on glioblastoma cells appears to modulate cell differentiation rather than to kill the cells.