A functional role for eicosanoid-lysophospholipids in activating monocyte signaling.

Autor: Liu GY; Department of Chemistry, Washington University, Saint Louis, Missouri, USA; Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA., Moon SH; Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA., Jenkins CM; Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA., Sims HF; Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA., Guan S; Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA., Gross RW; Department of Chemistry, Washington University, Saint Louis, Missouri, USA; Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA; Developmental Biology, Washington University School of Medicine, Saint Louis, Missouri, USA; Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA. Electronic address: rgross@wustl.edu.
Jazyk: angličtina
Zdroj: The Journal of biological chemistry [J Biol Chem] 2020 Aug 21; Vol. 295 (34), pp. 12167-12180. Date of Electronic Publication: 2020 Jul 08.
DOI: 10.1074/jbc.RA120.013619
Abstrakt: Recently, eicosanoid-lysophospholipids were identified as novel metabolites generated from the direct cyclooxygenase- or lipoxygenase-catalyzed oxidation of 2-arachidonoyl-lysophospholipids produced from either phospholipase A 1 -mediated hydrolysis of diacyl arachidonoyl-phospholipids or through the cytochrome c -catalyzed oxidative hydrolysis of the vinyl ether linkage of arachidonoyl-plasmalogens. Although the metabolic pathways generating eicosanoid-lysophospholipids have been increasingly appreciated, the signaling functions of eicosanoid-lysophospholipids remain largely unknown. Herein, we demonstrate that 2-12( S )-HETE-lysophospholipids as well as nonesterified 12( S )-HETE are potent lipid mediators that activate THP-1 human monocytic cells to generate tumor necrosis factor α (TNFα) and interleukin 8 (IL8). Remarkably, low nanomolar concentrations of 12( S )-HETE-lysophospholipids, but not other oxidized signaling lipids examined activated THP-1 cells resulting in the production of large amounts of TNFα. Moreover, TNFα release induced by 12( S )-HETE-lysophospholipids was inhibited by the TNFα converting enzyme inhibitor TAPI-0 indicating normal processing of TNFα in THP-1 cells stimulated with these agonists. Western blotting analyses revealed that 12( S )-HETE-lysophospholipids activated the phosphorylation of NFκB p65, suggesting activation of the canonical NFκB signaling pathway. Importantly, activation of THP-1 cells to release TNFα was stereoselective with 12( S )-HETE favored over 12( R )-HETE. Furthermore, the EC 50 of 2-12( S )-HETE-lysophosphatidylcholine in activating THP-1 cells was 2.1 nm, whereas the EC 50 of free 12( S )-HETE was 23 nm Additionally, lipid extracts of activated platelets were separated by RP-HPLC demonstrating the coelution of 12( S )-HETE with fractions initiating TNFα release. Collectively, these results demonstrate the potent signaling properties of 2-12( S )-HETE-lysophospholipids and 12( S )-HETE by their ability to release TNFα and activate NFκB signaling thereby revealing a previously unknown role of 2-12( S )-HETE-lysophospholipids in mediating inflammatory responses.
Competing Interests: Conflict of interest—The authors declare they have no conflict of interest.
(© 2020 Liu et al.)
Databáze: MEDLINE
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