Regulation of Tumor Necrosis Factor-α and IL-1β Synthesis by Thromboxane A2 in Nonadherent Human Monocytes

Gillian Caughey, Marc Pouliot, Leslie G. Cleland, Michael J. James

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106 Citations (Scopus)

Abstract

Synthesis of TNF-α and IL-1β 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-α or IL-1β, even though the addition of PGE2 to these treated cells dose-dependently inhibited TNF-α and IL-1β 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-β (61 ± 4.3%; n = 8; p < 0.001) and IL-1β (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-α and IL-1β 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-α (67 ± 2.4% and 65 ± 2.7%, respectively; n = 8; p < 0.001) and IL-1β (59 ± 3.3% and 70 ± 1.2%, respectively; n = 8; p < 0.001). Treatment with CI resulted in a partial decrease in TNF-α mRNA levels (60 ± 12.0%; n = 4), but had little or no effect on IL-1β mRNA levels. These novel observations implicate TXA2 as an important paracrine or autocrine facilitator of TNF-α and IL-1β production in stimulated human monocytes and suggest that levels of TNF-α and IL-1β synthesis are determined in part by the balance between TXA2 and PGE2 production in human monocytes.

LanguageEnglish
Pages351-358
Number of pages8
JournalJournal of Immunology
Volume158
Issue number1
Publication statusPublished - 1 Jan 1997
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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