CYP2C19 Contributes to THP-1-Cell-Derived M2 Macrophage Polarization by Producing 11,12- and 14,15-Epoxyeicosatrienoic Acid, Agonists of the PPARγ Receptor
Although the functional roles of M1 and M2 macrophages in the immune response and drug resistance are important, the expression and role of cytochrome P450s (CYPs) in these cells remain largely unknown. Differential expression of the 12 most common CYPs (CYP1A1, 1A2, 1B1, 2B6, 2C8, 2C9, 2C19, 2D6, 2...
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MDPI AG
2023-04-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/16/4/593 |
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| author | Hee Young Cho Sangzin Ahn Yong-Soon Cho Su-Kil Seo Dong Hyun Kim Jae-Gook Shin Su-Jun Lee |
| author_facet | Hee Young Cho Sangzin Ahn Yong-Soon Cho Su-Kil Seo Dong Hyun Kim Jae-Gook Shin Su-Jun Lee |
| author_sort | Hee Young Cho |
| collection | DOAJ |
| description | Although the functional roles of M1 and M2 macrophages in the immune response and drug resistance are important, the expression and role of cytochrome P450s (CYPs) in these cells remain largely unknown. Differential expression of the 12 most common CYPs (CYP1A1, 1A2, 1B1, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 2J2, 3A4, and 3A5) were screened in THP-1-cell-derived M1 and M2 macrophages using reverse transcription PCR. CYP2C19 was highly expressed in THP-1-cell-derived M2 macrophages, but it was negligibly expressed in THP-1-cell-derived M1 macrophages at the mRNA and protein levels as analyzed by reverse transcription quantitative PCR and Western blot, respectively. CYP2C19 enzyme activity was also very high in THP-1-cell-derived M2 compared to M1 macrophages (> 99%, <i>p</i> < 0.01), which was verified using inhibitors of CYP2C19 activity. Endogenous levels of the CYP2C19 metabolites 11,12-epoxyeicosatrienoic acid (11,12-EET) and 14,15-EET were reduced by 40% and 50% in cells treated with the CYP2C19 inhibitor and by 50% and 60% in the culture medium, respectively. Both 11,12-EET and 14,15-EET were identified as PPARγ agonists in an in vitro assay. When THP-1-cell-derived M2 cells were treated with CYP2C19 inhibitors, 11,12- and 14,15-EETs were significantly reduced, and in parallel with the reduction of these CYP2C19 metabolites, the expression of M2 cell marker genes was also significantly decreased (<i>p</i> < 0.01). Therefore, it was suggested that CYP2C19 may contribute to M2 cell polarization by producing PPARγ agonists. Further studies are needed to understand the endogenous role of CYP2C19 in M2 macrophages with respect to immunologic function and cell polarization. |
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| issn | 1424-8247 |
| language | English |
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| spelling | doaj.art-2e9388e61ed54dc8b3c4ee146662c3d22023-11-17T20:51:07ZengMDPI AGPharmaceuticals1424-82472023-04-0116459310.3390/ph16040593CYP2C19 Contributes to THP-1-Cell-Derived M2 Macrophage Polarization by Producing 11,12- and 14,15-Epoxyeicosatrienoic Acid, Agonists of the PPARγ ReceptorHee Young Cho0Sangzin Ahn1Yong-Soon Cho2Su-Kil Seo3Dong Hyun Kim4Jae-Gook Shin5Su-Jun Lee6Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Inje University, Busan 47392, Republic of KoreaDepartment of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Inje University, Busan 47392, Republic of KoreaDepartment of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Inje University, Busan 47392, Republic of KoreaCenter for Personalized Precision Medicine of Tuberculosis, Inje University College of Medicine, Inje University, Busan 47392, Republic of KoreaDepartment of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Inje University, Busan 47392, Republic of KoreaDepartment of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Inje University, Busan 47392, Republic of KoreaDepartment of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Inje University, Busan 47392, Republic of KoreaAlthough the functional roles of M1 and M2 macrophages in the immune response and drug resistance are important, the expression and role of cytochrome P450s (CYPs) in these cells remain largely unknown. Differential expression of the 12 most common CYPs (CYP1A1, 1A2, 1B1, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 2J2, 3A4, and 3A5) were screened in THP-1-cell-derived M1 and M2 macrophages using reverse transcription PCR. CYP2C19 was highly expressed in THP-1-cell-derived M2 macrophages, but it was negligibly expressed in THP-1-cell-derived M1 macrophages at the mRNA and protein levels as analyzed by reverse transcription quantitative PCR and Western blot, respectively. CYP2C19 enzyme activity was also very high in THP-1-cell-derived M2 compared to M1 macrophages (> 99%, <i>p</i> < 0.01), which was verified using inhibitors of CYP2C19 activity. Endogenous levels of the CYP2C19 metabolites 11,12-epoxyeicosatrienoic acid (11,12-EET) and 14,15-EET were reduced by 40% and 50% in cells treated with the CYP2C19 inhibitor and by 50% and 60% in the culture medium, respectively. Both 11,12-EET and 14,15-EET were identified as PPARγ agonists in an in vitro assay. When THP-1-cell-derived M2 cells were treated with CYP2C19 inhibitors, 11,12- and 14,15-EETs were significantly reduced, and in parallel with the reduction of these CYP2C19 metabolites, the expression of M2 cell marker genes was also significantly decreased (<i>p</i> < 0.01). Therefore, it was suggested that CYP2C19 may contribute to M2 cell polarization by producing PPARγ agonists. Further studies are needed to understand the endogenous role of CYP2C19 in M2 macrophages with respect to immunologic function and cell polarization.https://www.mdpi.com/1424-8247/16/4/593cytochrome P450CYP2C19M2 macrophagemetabolismPPAR gammaEETs |
| spellingShingle | Hee Young Cho Sangzin Ahn Yong-Soon Cho Su-Kil Seo Dong Hyun Kim Jae-Gook Shin Su-Jun Lee CYP2C19 Contributes to THP-1-Cell-Derived M2 Macrophage Polarization by Producing 11,12- and 14,15-Epoxyeicosatrienoic Acid, Agonists of the PPARγ Receptor Pharmaceuticals cytochrome P450 CYP2C19 M2 macrophage metabolism PPAR gamma EETs |
| title | CYP2C19 Contributes to THP-1-Cell-Derived M2 Macrophage Polarization by Producing 11,12- and 14,15-Epoxyeicosatrienoic Acid, Agonists of the PPARγ Receptor |
| title_full | CYP2C19 Contributes to THP-1-Cell-Derived M2 Macrophage Polarization by Producing 11,12- and 14,15-Epoxyeicosatrienoic Acid, Agonists of the PPARγ Receptor |
| title_fullStr | CYP2C19 Contributes to THP-1-Cell-Derived M2 Macrophage Polarization by Producing 11,12- and 14,15-Epoxyeicosatrienoic Acid, Agonists of the PPARγ Receptor |
| title_full_unstemmed | CYP2C19 Contributes to THP-1-Cell-Derived M2 Macrophage Polarization by Producing 11,12- and 14,15-Epoxyeicosatrienoic Acid, Agonists of the PPARγ Receptor |
| title_short | CYP2C19 Contributes to THP-1-Cell-Derived M2 Macrophage Polarization by Producing 11,12- and 14,15-Epoxyeicosatrienoic Acid, Agonists of the PPARγ Receptor |
| title_sort | cyp2c19 contributes to thp 1 cell derived m2 macrophage polarization by producing 11 12 and 14 15 epoxyeicosatrienoic acid agonists of the pparγ receptor |
| topic | cytochrome P450 CYP2C19 M2 macrophage metabolism PPAR gamma EETs |
| url | https://www.mdpi.com/1424-8247/16/4/593 |
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