Prostaglandins antagonize fibroblast proliferation stimulated by tumor necrosis factor.
Tumor necrosis factor (TNF) is known to be a mitogen for human diploid FS-4 fibroblasts. We have shown in an earlier study (Hori et al. (1989) J. Cell. Physiol. 141, 275-280) that indomethacin further enhances the cell proliferation stimulated by TNF. Since indomethacin inhibits the activity of cyclooxygenase, the role of prostaglandins in TNF-stimulated cell growth was examined. Cell growth stimulated by TNF and indomethacin was inhibited by exogenously added prostaglandins (PGE2, PGF2 alpha, and PGD2), among which PGE2 caused the greatest inhibition of cell growth. Treatment of FS-4 cells with 10 ng/ml TNF resulted in the release of prostaglandins (PGE2, 6-keto-PGF1 alpha, PGA2, PGD2, and PGF2 alpha) 2 to 4 fold over that of untreated cells. The amount of all these prostaglandins increased in a time-dependent manner over 6 h after treatment. In both TNF-treated and control cells, PGE2 was released as the predominant prostaglandin. Furthermore, when PGE2 production and DNA synthesis were determined in FS-4 cells treated with increasing doses of indomethacin, these two cellular responses were inversely affected by indomethacin. These data show that prostaglandins induced by TNF antagonize growth stimulatory action of TNF.
Hori
T
T
Department of Biochemistry, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan.
Yamanaka
Y
Y
Hayakawa
M
M
Shibamoto
S
S
Tsujimoto
M
M
Oku
N
N
Ito
F
F
D001095:Arachidonic Acids / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D004261:DNA Replication / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007700:Kinetics; D011453:Prostaglandins / Q000378:metabolism / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D001095:Arachidonic Acids; D011453:Prostaglandins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007213:Indomethacin