Involvement of prostaglandin-producing pathway in the cytotoxic action of tumor necrosis factor.
To elucidate the cytotoxic mechanism of tumor necrosis factor (TNF), we isolated TNF-resistant sublines of L929 cells. As compared with L929 cells, TNF-resistant cells retained similar number and affinity of TNF-binding sites, and showed a similar growth rate. TNF stimulated arachidonate release from L929 cells, while no stimulation was observed at all in TNF-resistant cells tested. The cytotoxic action of TNF on L929 cells was inhibited by indomethacin, suggesting that prostaglandin may be involved in the action. Therefore, TNF-stimulated prostaglandin production was examined in L929 and TNF-resistant sublines. The amount of PGE2 produced by L929 cells was increased more than 5-fold after the addition of TNF, whereas the amount of PGE2 did not change in the resistant sublines following addition of the factor. TNF-stimulated arachidonate release and PGE2 production were reversed by islet-activating protein (IAP)-treatment of L929 cells. These results suggest that arachidonate release and subsequent prostaglandin production are important for the cytotoxic action of TNF and that these processes are mediated by GTP-binding protein (G protein) that is coupled to the TNF-receptor.
Hayakawa
M
M
Department of Biochemistry, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan.
Oku
N
N
Takagi
T
T
Hori
T
T
Shibamoto
S
S
Yamanaka
Y
Y
Takeuchi
K
K
Tsujimoto
M
M
Ito
F
F
D000818:Animals; D016718:Arachidonic Acid / Q000096:biosynthesis*; D001665:Binding Sites; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D015232:Dinoprostone / Q000096:biosynthesis*; D005347:Fibroblasts; D019204:GTP-Binding Proteins / Q000378:metabolism; D051379:Mice; D009154:Mutation; D037342:Pertussis Toxin; D012641:Selection, Genetic; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D014409:Tumor Necrosis Factor-alpha; D010566:Virulence Factors, Bordetella; D016718:Arachidonic Acid; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D015232:Dinoprostone