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 E-2, intracellular platelet-activating factor (PAF) and interleukin-6. However, no PAT 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 E-2 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 E-2. 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 E-2 and intracellular PAF participate in the thapsigargin-induced increase in the interleukin-6 mRNA level and interleukin-6 production by rat peritoneal macrophages. (C) 2002 Elsevier science B.V. All rights reserved.