cPLA<sub>2</sub>α Enzyme Inhibition Attenuates Inflammation and Keratinocyte Proliferation
As a regulator of cellular inflammation and proliferation, cytosolic phospholipase A<sub>2</sub> α (cPLA<sub>2</sub>α) is a promising therapeutic target for psoriasis; indeed, the cPLA<sub>2</sub>α inhibitor AVX001 has shown efficacy against plaque psoriasis in a...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-10-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/10/10/1402 |
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| author | Felicity J. Ashcroft Nur Mahammad Helene Midtun Flatekvål Astrid J. Feuerherm Berit Johansen |
| author_facet | Felicity J. Ashcroft Nur Mahammad Helene Midtun Flatekvål Astrid J. Feuerherm Berit Johansen |
| author_sort | Felicity J. Ashcroft |
| collection | DOAJ |
| description | As a regulator of cellular inflammation and proliferation, cytosolic phospholipase A<sub>2</sub> α (cPLA<sub>2</sub>α) is a promising therapeutic target for psoriasis; indeed, the cPLA<sub>2</sub>α inhibitor AVX001 has shown efficacy against plaque psoriasis in a phase I/IIa clinical trial. To improve our understanding of the anti-psoriatic properties of AVX001, we sought to determine how the compound modulates inflammation and keratinocyte hyperproliferation, key characteristics of the psoriatic epidermis. We measured eicosanoid release from human peripheral blood mononuclear cells (PBMC) and immortalized keratinocytes (HaCaT) and studied proliferation in HaCaT grown as monolayers and stratified cultures. We demonstrated that inhibition of cPLA<sub>2</sub>α using AVX001 produced a balanced reduction of prostaglandins and leukotrienes; significantly limited prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) release from both PBMC and HaCaT in response to pro-inflammatory stimuli; attenuated growth factor-induced arachidonic acid and PGE<sub>2</sub> release from HaCaT; and inhibited keratinocyte proliferation in the absence and presence of exogenous growth factors, as well as in stratified cultures. These data suggest that the anti-psoriatic properties of AVX001 could result from a combination of anti-inflammatory and anti-proliferative effects, probably due to reduced local eicosanoid availability. |
| first_indexed | 2024-03-10T15:53:25Z |
| format | Article |
| id | doaj.art-f495d432e2c446da91063555d0f5ffa2 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T15:53:25Z |
| publishDate | 2020-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-f495d432e2c446da91063555d0f5ffa22023-11-20T15:55:04ZengMDPI AGBiomolecules2218-273X2020-10-011010140210.3390/biom10101402cPLA<sub>2</sub>α Enzyme Inhibition Attenuates Inflammation and Keratinocyte ProliferationFelicity J. Ashcroft0Nur Mahammad1Helene Midtun Flatekvål2Astrid J. Feuerherm3Berit Johansen4Department of Biology, Norwegian University of Science and Technology, Realfagbygget, 7491 Trondheim, NorwayDepartment of Biology, Norwegian University of Science and Technology, Realfagbygget, 7491 Trondheim, NorwayDepartment of Biology, Norwegian University of Science and Technology, Realfagbygget, 7491 Trondheim, NorwayDepartment of Biology, Norwegian University of Science and Technology, Realfagbygget, 7491 Trondheim, NorwayDepartment of Biology, Norwegian University of Science and Technology, Realfagbygget, 7491 Trondheim, NorwayAs a regulator of cellular inflammation and proliferation, cytosolic phospholipase A<sub>2</sub> α (cPLA<sub>2</sub>α) is a promising therapeutic target for psoriasis; indeed, the cPLA<sub>2</sub>α inhibitor AVX001 has shown efficacy against plaque psoriasis in a phase I/IIa clinical trial. To improve our understanding of the anti-psoriatic properties of AVX001, we sought to determine how the compound modulates inflammation and keratinocyte hyperproliferation, key characteristics of the psoriatic epidermis. We measured eicosanoid release from human peripheral blood mononuclear cells (PBMC) and immortalized keratinocytes (HaCaT) and studied proliferation in HaCaT grown as monolayers and stratified cultures. We demonstrated that inhibition of cPLA<sub>2</sub>α using AVX001 produced a balanced reduction of prostaglandins and leukotrienes; significantly limited prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) release from both PBMC and HaCaT in response to pro-inflammatory stimuli; attenuated growth factor-induced arachidonic acid and PGE<sub>2</sub> release from HaCaT; and inhibited keratinocyte proliferation in the absence and presence of exogenous growth factors, as well as in stratified cultures. These data suggest that the anti-psoriatic properties of AVX001 could result from a combination of anti-inflammatory and anti-proliferative effects, probably due to reduced local eicosanoid availability.https://www.mdpi.com/2218-273X/10/10/1402cPLA<sub>2</sub>αpsoriasisproliferationanti-inflammatory |
| spellingShingle | Felicity J. Ashcroft Nur Mahammad Helene Midtun Flatekvål Astrid J. Feuerherm Berit Johansen cPLA<sub>2</sub>α Enzyme Inhibition Attenuates Inflammation and Keratinocyte Proliferation Biomolecules cPLA<sub>2</sub>α psoriasis proliferation anti-inflammatory |
| title | cPLA<sub>2</sub>α Enzyme Inhibition Attenuates Inflammation and Keratinocyte Proliferation |
| title_full | cPLA<sub>2</sub>α Enzyme Inhibition Attenuates Inflammation and Keratinocyte Proliferation |
| title_fullStr | cPLA<sub>2</sub>α Enzyme Inhibition Attenuates Inflammation and Keratinocyte Proliferation |
| title_full_unstemmed | cPLA<sub>2</sub>α Enzyme Inhibition Attenuates Inflammation and Keratinocyte Proliferation |
| title_short | cPLA<sub>2</sub>α Enzyme Inhibition Attenuates Inflammation and Keratinocyte Proliferation |
| title_sort | cpla sub 2 sub α enzyme inhibition attenuates inflammation and keratinocyte proliferation |
| topic | cPLA<sub>2</sub>α psoriasis proliferation anti-inflammatory |
| url | https://www.mdpi.com/2218-273X/10/10/1402 |
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