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  • Title: Possible participation of intracellular platelet-activating factor in tumor necrosis factor-alpha production by rat peritoneal macrophages.
    Author: Yamada M, Tanimoto A, Ichinowatari G, Yaginuma H, Ohuchi K.
    Journal: Eur J Pharmacol; 1999 Jun 25; 374(3):341-50. PubMed ID: 10422778.
    Abstract:
    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.
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