Regulation of tumor necrosis factor-alpha and IL-1 beta synthesis by thromboxane A2 in nonadherent human monocytes.
Synthesis of TNF-alpha and IL-1beta, by monocytes/macrophages can be partially regulated by the eicosanoid, PGE2. We report here that inhibition of both PGE2 and thromboxane A2 (TXA2) synthesis by a prostaglandin H synthase inhibitor, NS-398, had no effect on the synthesis of either TNF-alpha or IL-1beta, even though the addition of PGE2 to these treated cells dose-dependently inhibited TNF-alpha and IL-1beta synthesis. Because TXA2 is a major eicosanoid product of stimulated human monocytes, we examined its influence on cytokine production. Inhibition of thromboxane synthase by carboxyheptyl imidazole (CI) resulted in inhibition of TNF-alpha (61 +/- 4.3%; n = 8; p < 0.001) and IL-1beta (54 +/- 4.2%; n = 8; p < 0.001) synthesis by serum-treated zymosan-stimulated nonadherent human monocytes. This effect was observed when cytokine production was measured by ELISA or bioactivity assays. Furthermore, the addition of a TXA2 agonist, carbocyclic TXA2, to CI-treated monocytes dose-dependently restored the levels of TNF-alpha and IL-1beta synthesis to those found with serum-treated zymosan stimulation alone. Inhibition of TXA2 activity by the thromboxane receptor antagonists, pinane TXA2 or SQ 29,548, also inhibited the production of TNF-alpha (67 +/- 2.4% and 65 +/- 2.7%, respectively; n = 8; p < 0.001) and IL-1beta (59 +/- 3.3% and 70 +/- 1.2%, respectively; n = 8; p < 0.001). Treatment with CI resulted in a partial decrease in TNF-alpha mRNA levels (60 +/- 12.0%; n = 4), but had little or no effect on IL-1beta mRNA levels. These novel observations implicate TXA2 as an important paracrine or autocrine facilitator of TNF-alpha and IL-1beta production in stimulated human monocytes and suggest that levels of TNF-alpha and IL-1beta synthesis are determined in part by the balance between TXA2 and PGE2 production in human monocytes.
Caughey
G E
GE
Rheumatology Unit, Royal Adelaide Hospital, South Australia.
Pouliot
M
M
Cleland
L G
LG
James
M J
MJ
D002478:Cells, Cultured; D015232:Dinoprostone / Q000096:biosynthesis / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D013928:Thromboxane A2 / Q000096:biosynthesis / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000187:drug effects* / Q000235:genetics
D007375:Interleukin-1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007975:Leukotriene B4; D013928:Thromboxane A2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone