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. 2016 Feb 3;11(2):e0148306.
doi: 10.1371/journal.pone.0148306. eCollection 2016.

Differential Regulation of Eicosanoid and Endocannabinoid Production by Inflammatory Mediators in Human Choriodecidua

Affiliations

Differential Regulation of Eicosanoid and Endocannabinoid Production by Inflammatory Mediators in Human Choriodecidua

M D Mitchell et al. PLoS One. .

Abstract

An increase in intrauterine prostaglandin production is critical for the onset and progression of labor in women and indeed all mammalian species studied. Endocannabinoids can act as substrates for enzymes of the prostaglandin biosynthetic pathways and can be utilized to generate other related compounds such as prostamides. The end products are indistinguishable by radioimmunoassay. We have separated such compounds by mass spectrometry. We now show that inflammatory stimuli such as LPS and proinflammatory cytokines act differentially on these pathways in human choriodecidua and preferentially create drive through to prostaglandin end products. These findings create doubt about the interpretation of data on prostaglandin biosynthesis in intrauterine tissues from pregnant women especially in the presence of an infection. The possibility is raised that separation of these products might reduce variability in results and lead to potential uses for their measurement in the diagnosis of preterm labor.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Endocannabinoid pathway.
Endocannabinoid pathway giving rise to prostaglandins glycerol esters, prostaglandins and prostamides.
Fig 2
Fig 2. Chromatogram for analysis of prostaglandins, endocannabinoids, and prostamides by LC-MS/MS.
Representative chromatogram with gradient conditions, showing polarity switching periods for the concomitant analysis of prostaglandins, endocannabinoids, and prostamides by LC-MS/MS in (a) 100 pmol/L standard and (b) 10 μL extract of placental choriodecidua.
Fig 3
Fig 3. Standard Curve.
Linear calibration range of prostaglandins, endocannabinoids, and prostamides (0.01–5.0 nmol/L).
Fig 4
Fig 4. Production of PGs, Prostamides and Endocannabinoids by LPS treated CD explants (control vs 10μg/mL LPS).
LC-MS/MS detection of (a) prostaglandins (PGF, PGE2 and PGFM), (b) prostamides (PGF-EA and PGE2-EA) and (c) endocannabinoids (AEA and 2-AG) production by choriodecidual explants treated with 10μg/mL LPS. Dashed line represents the lower limit of quantitation (LLQ). Significant differences in production of the compounds were determined by Wilcoxon signed-rank test. and significance was defined as P<0.05 (* on graphs). Data were presented as the mean ± S.E.M.
Fig 5
Fig 5. Production of PGs, Prostamides and Endocannabinoids by IL-1β treated CD explants (control vs 10ng/mL IL-1β).
LC-MS/MS detection of prostaglandins (PGF, PGE2 and PGFM), (b) prostamides (PGF-EA and PGE2-EA) and (c) endocannabinoids (AEA and 2-AG) production by choriodecidual explants treated with 10ng/mL IL-1β. Dashed line represents the lower limit of quantitation (LLQ). Significant differences in production of the compounds were determined by Wilcoxon signed-rank test and significance was defined as P<0.05 (* on graphs). Data were presented as the mean ± S.E.M.
Fig 6
Fig 6. Production of PGs, Prostamides and Endocannabinoids by TNF-α treated CD explants (control vs 10ng/mL TNF-α).
LC-MS/MS detection of prostaglandins (PGF, PGE2 and PGFM), (b) prostamides (PGF-EA and PGE2-EA) and (c) endocannabinoids (AEA and 2-AG) production by choriodecidual explants treated with 100ng/mL TNF-α. Dashed line represents the lower limit of quantitation (LLQ). Significant differences in production of the compounds were determined by Wilcoxon signed-rank test and significance was defined as P<0.05 (* on graphs). Data were presented as the mean ± S.E.M.
Fig 7
Fig 7. Ratio of Prostaglandin to prostaglandin ethanolamide production by LPS, IL-1β, or TNF-α treated choriodecidual explants.
Production of eicosanoids (mean ratio of PGE2 and PGF to ethanolamide metabolites, 25% and 75% quantiles with 95% confidence intervals, n = 5) by term choriodecidua after treatment with LPS, IL-1β, or TNF-α (in Blue; control in black). Data were analyzed using Wilcoxon signed-ranks tests.

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Grants and funding

MDM received funding from Therapeutics Innovation Australia–Queensland Node, the National Collaborative Research Infrastructure Strategy and SmartFutures. HNP was supported by The Lalor Foundation Postdoctoral Fellowship.