Possible participation of intracellular platelet-activating factor in tumor necrosis factor-alpha production by rat peritoneal macrophages.
Stimulation of rat peritoneal macrophages by thapsigargin (46.1 nM) increased levels of tumor necrosis factor-alpha and prostaglandin E2 in the conditioned medium. Platelet-activating factor (PAF) was not detected in the conditioned medium, but the level of cell-associated PAF was increased transiently by thapsigargin. The PAF receptor antagonists such as E6123 ((S)-(+)-6-(2-chlorophenyl)-3-cyclopro-panecarbonyl-8,11-dim ethyl-2,3,4,5-tetrahydro-8 H-pyrido[4',3':4,5]thieno [3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine), L-652,73 1 (2,5-bis(3,4,5-trimethoxyphenyl) tetrahydrofuran) and CV-6209 (2-[N-acetyl-N-(2-methoxy-3-octadecyl-carbamoyloxy propoxycarbonyl)aminomethyl]-1-ethylpyridinium chloride) inhibited thapsigargin-induced production of tumor necrosis factor-alpha. The cyclooxygenase inhibitor indomethacin inhibited prostaglandin E2 production, and further enhanced thapsigargin-induced tumor necrosis factor-alpha production in parallel with further increase in cell-associated PAF production. The enhancement of tumor necrosis factor-alpha production induced by thapsigargin plus indomethacin was also inhibited by E6123, L-652,731 and CV-6209. However, exogenously added PAF up to 100 nM did not stimulate production of tumor necrosis factor-alpha. The level of tumor necrosis factor-alpha mRNA was increased by thapsigargin, but was lowered by the PAF receptor antagonist E6123, suggesting that the inhibition of tumor necrosis factor-alpha production by the PAF receptor antagonist is induced at the level of mRNA for tumor necrosis factor-alpha. These findings suggested that concurrently produced cell-associated PAF in thapsigargin-stimulated macrophages up-regulates production of tumor necrosis factor-alpha by acting as an intracellular signaling molecule and the PAF receptor antagonists might penetrate into the cells and antagonize the action of intracellular PAF.
Yamada
M
M
Department of Pathophysiological Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan.
Tanimoto
A
A
Ichinowatari
G
G
Yaginuma
H
H
Ohuchi
K
K
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D002478:Cells, Cultured; D015232:Dinoprostone / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005663:Furans / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000187:drug effects / Q000378:metabolism* / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019284:Thapsigargin / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics
D001381:Azepines; D004791:Enzyme Inhibitors; D005663:Furans; D007093:Imidazoles; D009943:Organophosphorus Compounds; D010972:Platelet Activating Factor; D011726:Pyridinium Compounds; D012333:RNA, Messenger; C093303:SK&F 98625; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; C053321:CV 6209; C068033:E 6123; D019284:Thapsigargin; C047504:2,5-bis(3,4,5-trimethoxyphenyl)tetrahydrofuran; D015232:Dinoprostone; D007213:Indomethacin