Participation of prostaglandin E2 and platelet-activating factor in thapsigargin-induced production of interleukin-6.
Incubation of rat peritoneal macrophages in the presence of thapsigargin increased production of prostaglandin E2, intracellular platelet-activating factor (PAF) and interleukin-6. However, no PAF was detected in the conditioned medium. In the presence of SK&F 98625 (diethyl 7-(3,4,5-triphenyl-2-oxo-2,3-dihydroimidazol-1-yl)heptane phosphonate), a CoA-independent transacylase inhibitor, the thapsigargin-induced increases in the interleukin-6 mRNA level and interleukin-6 production were suppressed in a concentration-dependent manner. This inhibitor also suppressed the production of prostaglandin E2 and intracellular PAF. The PAF receptor antagonists such as E6123 ((S)-(+)-6-(2-chlorophenyl)-3-cyclopropanecarbonyl-8,11-dimethyl-2,3,4,5-tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo [4,3-a][1,4]diazepine) and L-652,731 (2,5-bis(3,4,5-trimethylphenyl)tetrahydrofuran) partially inhibited the thapsigargin-induced increase in the levels of interleukin-6 mRNA and interleukin-6 protein. The SK&F 98625-induced suppression of interleukin-6 mRNA accumulation and interleukin-6 production was partially restored by addition of exogenous prostaglandin E2. However, exogenous PAF failed to reverse the suppression suggesting that the intracellular PAF does not act in an autocrine mechanism. These findings suggested that the concurrently produced prostaglandin E2 and intracellular PAF participate in the thapsigargin-induced increase in the interleukin-6 mRNA level and interleukin-6 production by rat peritoneal macrophages.
Ichinowatari
Gaku
G
Laboratory of Pathophysiological Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan.
Yamada
Masateru
M
Yaginuma
Hiroshi
H
Tsuyuki
Kousei
K
Tanimoto
Atsuo
A
Ohuchi
Kazuo
K
D000123:Acetyltransferases / Q000037:antagonists & inhibitors; D051051:Acyl-Carrier Protein S-Acetyltransferase; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D002478:Cells, Cultured; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005663:Furans / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000502:physiology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D019284:Thapsigargin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology; D000093242:Interleukin-6 Inhibitors
D000123:Acetyltransferases; D051051:Acyl-Carrier Protein S-Acetyltransferase; D001381:Azepines; D015232:Dinoprostone; D004791:Enzyme Inhibitors; D005663:Furans; D007093:Imidazoles; D007213:Indomethacin; D015850:Interleukin-6; D009943:Organophosphorus Compounds; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D019284:Thapsigargin; D014230:Triazoles; D000093242:Interleukin-6 Inhibitors; C093303:SK&F 98625; C039351:platelet activating factor receptor; C068033:E 6123; C047504:2,5-bis(3,4,5-trimethoxyphenyl)tetrahydrofuran