Endogenous epoxygenases are modulators of monocyte/macrophage activity.
<h4>Background</h4>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.<h4>...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2011-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0026591&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849727677474275328 |
|---|---|
| author | Jonas Bystrom Jessica A Wray Mary C Sugden Mark J Holness Karen E Swales Timothy D Warner Matthew L Edin Darryl C Zeldin Derek W Gilroy David Bishop-Bailey |
| author_facet | Jonas Bystrom Jessica A Wray Mary C Sugden Mark J Holness Karen E Swales Timothy D Warner Matthew L Edin Darryl C Zeldin Derek W Gilroy David Bishop-Bailey |
| author_sort | Jonas Bystrom |
| collection | DOAJ |
| description | <h4>Background</h4>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.<h4>Methodology/principal findings</h4>When transfected in vitro, CYP2J2 is an efficient activator of anti-inflammatory pathways through the nuclear receptor peroxisome proliferator-activated receptor (PPAR) α. Human monocytes and macrophages contain PPARα 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 TNFα, and can be reversed by either add back of the endogenous epoxygenase products and PPARα ligand 11,12- epoxyeicosatrienoic acid (EET) or the addition of the selective synthetic PPARα ligand GW7647. In alternatively activated (IL-4-treated) monocytes, in contrast to classically activated cells, epoxygenase inhibition decreased TNFα release. Epoxygenases can be pro-inflammatory via superoxide anion production. The suppression of TNFα by SKF525A in the presence of IL-4 was associated with a reduction in superoxide anion generation and reproduced by the superoxide dismutase MnCl(2). Similar to these acute activation studies, in monocyte derived macrophages, epoxygenase inhibition elevates M1 macrophage TNFα mRNA and further decreases M2 macrophage TNFα.<h4>Conclusions/significance</h4>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. |
| format | Article |
| id | doaj-art-48caab00b23e41049a4c13ab8e5fb4af |
| institution | DOAJ |
| issn | 1932-6203 |
| language | English |
| publishDate | 2011-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-48caab00b23e41049a4c13ab8e5fb4af2025-08-20T03:09:47ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-01610e2659110.1371/journal.pone.0026591Endogenous epoxygenases are modulators of monocyte/macrophage activity.Jonas BystromJessica A WrayMary C SugdenMark J HolnessKaren E SwalesTimothy D WarnerMatthew L EdinDarryl C ZeldinDerek W GilroyDavid Bishop-Bailey<h4>Background</h4>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.<h4>Methodology/principal findings</h4>When transfected in vitro, CYP2J2 is an efficient activator of anti-inflammatory pathways through the nuclear receptor peroxisome proliferator-activated receptor (PPAR) α. Human monocytes and macrophages contain PPARα 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 TNFα, and can be reversed by either add back of the endogenous epoxygenase products and PPARα ligand 11,12- epoxyeicosatrienoic acid (EET) or the addition of the selective synthetic PPARα ligand GW7647. In alternatively activated (IL-4-treated) monocytes, in contrast to classically activated cells, epoxygenase inhibition decreased TNFα release. Epoxygenases can be pro-inflammatory via superoxide anion production. The suppression of TNFα by SKF525A in the presence of IL-4 was associated with a reduction in superoxide anion generation and reproduced by the superoxide dismutase MnCl(2). Similar to these acute activation studies, in monocyte derived macrophages, epoxygenase inhibition elevates M1 macrophage TNFα mRNA and further decreases M2 macrophage TNFα.<h4>Conclusions/significance</h4>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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0026591&type=printable |
| spellingShingle | Jonas Bystrom Jessica A Wray Mary C Sugden Mark J Holness Karen E Swales Timothy D Warner Matthew L Edin Darryl C Zeldin Derek W Gilroy David Bishop-Bailey Endogenous epoxygenases are modulators of monocyte/macrophage activity. PLoS ONE |
| title | Endogenous epoxygenases are modulators of monocyte/macrophage activity. |
| title_full | Endogenous epoxygenases are modulators of monocyte/macrophage activity. |
| title_fullStr | Endogenous epoxygenases are modulators of monocyte/macrophage activity. |
| title_full_unstemmed | Endogenous epoxygenases are modulators of monocyte/macrophage activity. |
| title_short | Endogenous epoxygenases are modulators of monocyte/macrophage activity. |
| title_sort | endogenous epoxygenases are modulators of monocyte macrophage activity |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0026591&type=printable |
| work_keys_str_mv | AT jonasbystrom endogenousepoxygenasesaremodulatorsofmonocytemacrophageactivity AT jessicaawray endogenousepoxygenasesaremodulatorsofmonocytemacrophageactivity AT marycsugden endogenousepoxygenasesaremodulatorsofmonocytemacrophageactivity AT markjholness endogenousepoxygenasesaremodulatorsofmonocytemacrophageactivity AT kareneswales endogenousepoxygenasesaremodulatorsofmonocytemacrophageactivity AT timothydwarner endogenousepoxygenasesaremodulatorsofmonocytemacrophageactivity AT matthewledin endogenousepoxygenasesaremodulatorsofmonocytemacrophageactivity AT darrylczeldin endogenousepoxygenasesaremodulatorsofmonocytemacrophageactivity AT derekwgilroy endogenousepoxygenasesaremodulatorsofmonocytemacrophageactivity AT davidbishopbailey endogenousepoxygenasesaremodulatorsofmonocytemacrophageactivity |