Bystrom, J;
Wray, JA;
Sugden, MC;
Holness, MJ;
Swales, KE;
Warner, TD;
Edin, ML;
... Bishop-Bailey, D; + view all
(2011)
Endogenous Epoxygenases Are Modulators of Monocyte/Macrophage Activity.
PLOS ONE
, 6
(10)
, Article e26591. 10.1371/journal.pone.0026591.
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Abstract
Background: Arachidonic acid is metabolized through three major metabolic pathways, the cyclooxygenase, lipoxygenase and CYP450 enzyme systems. Unlike cyclooxygenase and lipoxygenases, the role of CYP450 epoxygenases in monocyte/macrophage-mediated responses is not known.Methodology/Principal Findings: When transfected in vitro, CYP2J2 is an efficient activator of anti-inflammatory pathways through the nuclear receptor peroxisome proliferator-activated receptor (PPAR) alpha. Human monocytes and macrophages contain PPAR alpha and here we show they express the epoxygenases CYP2J2 and CYP2C8. Inhibition of constitutive monocyte epoxygenases using the epoxygenase inhibitor SKF525A induces cyclooxygenase (COX)-2 expression and activity, and the release of TNF alpha, and can be reversed by either add back of the endogenous epoxygenase products and PPAR alpha ligand 11,12-epoxyeicosatrienoic acid (EET) or the addition of the selective synthetic PPAR alpha ligand GW7647. In alternatively activated (IL-4-treated) monocytes, in contrast to classically activated cells, epoxygenase inhibition decreased TNF alpha release. Epoxygenases can be pro-inflammatory via superoxide anion production. The suppression of TNF alpha by SKF525A in the presence of IL-4 was associated with a reduction in superoxide anion generation and reproduced by the superoxide dismutase MnCl2. Similar to these acute activation studies, in monocyte derived macrophages, epoxygenase inhibition elevates M1 macrophage TNF alpha mRNA and further decreases M2 macrophage TNF alpha.Conclusions/Significance: In conclusion, epoxygenase activity represents an important endogenous pathway which limits monocyte activation. Moreover endogenous epoxygenases are immuno-modulators regulating monocyte/macrophage activation depending on the underlying activation state.
| Type: | Article |
|---|---|
| Title: | Endogenous Epoxygenases Are Modulators of Monocyte/Macrophage Activity |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pone.0026591 |
| Publisher version: | http://dx.doi.org/10.1371/journal.pone.0026591 |
| Language: | English |
| Additional information: | This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. This work was partly funded by grants from the British Heart Foundation (FS/04/075; BS/02/002; PG/08/070/25464), the Wellcome Trust (074361/Z/04/Z) and the Intramural Research Programs of the National Institutes of Health, NIEHS (to DZ), and European Community FP6 funding (LSHM-CT-2004-0050333). Derek Gilroy holds a Wellcome Trust Senior Fellowship. This work forms part of the research themes contributing to the translational research portfolio of Barts and the London Cardiovascular Biomedical Research Unit which is supported and funded by the National Institute of Health Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. |
| Keywords: | PROLIFERATOR-ACTIVATED RECEPTORS, KAPPA-B ACTIVITY, ENDOTHELIAL-CELLS, LAMINAR-FLOW, IN-VITRO, CYTOCHROME-P450, ACID, EXPRESSION, CYP2J2, GAMMA |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Experimental and Translational Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1333054 |
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