The Regulation of Interleukin-6 Secretion by Prostanoids and Members of the Tumor Necrosis Factor Superfamily in Fresh Villous Fragments of Term Human Placenta

Abstract

Objective: To determine whether prostanoids, nonsteroidal anti-inflammatory drugs (NSAIDs), and members of the tumor necrosis factor superfamily can regulate placental secretion of interleukin-6 (IL-6) and whether labor influences any such effects.

Methods: Villous fragments of term, human placenta were kept in culture for up to 4 hours, and IL-6 concentrations were measured in the supermatant. We assessed the effects of the following prostanoids: PGE₂, PGF_2α, thromboxane A₂ mimetic (U-46619), and carbacyclin, a stable prostacyclin analogue (all at 1 μM); NSAIDs: indomethacin (150 μM) or nimesulide (100 μM); and Fas ligand (5 ng/mL).

Results: Secretion (mean ± standard error) of IL-6 was, for control conditions, 1.92 ± 0.28 fmol/mg wet weight per 3 hours; for PGE₂, 3.57 ± 0.29 fmol/mg wet weight per 3 hours, P < .01; and for carbacyclin, 3.11 ± 0.44 fmol/mg wet weight per 3 hours, P < .01. Incubation with PGF_2α or the thromboxane A₂ analogue, U46619, had no effect on IL-6 secretion under these conditions. Fas ligand stimulated IL-6 secretion (3.06 ± 0.38 fmol/mg wet weight per 3 hours, P < .05). Labor did not alter the effects of prostanoids or FasL. The effects of NSAIDs were assessed over 4 hours. Secretion (median, interquartile range) was, under control conditions 3.26, 2.83-6.23 fmol/mg wet weight per 4 hours, with indomethacin 1.4, 1.28-3.21 (P < .05), and with nimesulide 0.75, 0.50-1.56 fmol/mg wet weight per 4 hours. The magnitude of the effect of Fas ligand in the presence of NSAIDs depended on whether the placentas were delivered before or after labor.

Conclusion: Prostanoids, NSAIDs, and the Fas ligand regulate placental IL-6 secretion. Although the effects of individual agents did not vary with the presence or absence of labor, modulation of IL-6 secretion by labor became apparent when agents were combined.

Keywords

Fetal inflammatory response prostanoids cytokines placenta

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