Key Points
4-OI reduces COX2 expression and inhibits PG production in macrophages.
DMF also attenuates COX2 expression in macrophages and decreases PGs.
The 4-OI– and DMF-induced decrease in COX2 and PGs is NRF2 independent.
Abstract
PGs are important proinflammatory lipid mediators, the significance of which is highlighted by the widespread and efficacious use of nonsteroidal anti-inflammatory drugs in the treatment of inflammation. 4-Octyl itaconate (4-OI), a derivative of the Krebs cycle–derived metabolite itaconate, has recently garnered much interest as an anti-inflammatory agent. In this article, we show that 4-OI limits PG production in murine macrophages stimulated with the TLR1/2 ligand Pam3CSK4. This decrease in PG secretion is due to a robust suppression of cyclooxygenase 2 (COX2) expression by 4-OI, with both mRNA and protein levels decreased. Dimethyl fumarate, a fumarate derivative used in the treatment of multiple sclerosis, with properties similar to itaconate, replicated the phenotype observed with 4-OI. We also demonstrate that the decrease in COX2 expression and inhibition of downstream PG production occurs in an NRF2-independent manner. Our findings provide a new insight into the potential of 4-OI as an anti-inflammatory agent and also identifies a novel anti-inflammatory function of dimethyl fumarate.
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Footnotes
This work was supported by grants from the European Research Council (834370), the Wellcome Trust (205455), and Science Foundation Ireland (12/IA/1531) (to L.A.J.O.). V.J.T. and V.B.O. were supported by a Ser Cymru Project Sepsis grant funded by the Welsh Government/European Union, European Regional Development Fund. V.B.O. is a Royal Society Wolfson Research Merit Award Holder.
The online version of this article contains supplemental material.
Abbreviations used in this article
- BMDM
- bone marrow–derived macrophage
- COX
- cyclooxygenase
- cPLA2
- cytoplasmic phospholipase A2
- DEM
- diethyl maleate
- DMF
- dimethyl fumarate
- EP
- E prostanoid receptor
- IRG1
- immune responsive gene 1
- LC
- liquid chromatography
- MS/MS
- tandem mass spectrometry
- NO
- nitric oxide
- 4-OI
- 4-octyl itaconate
- TXB2
- thromboxane B2.
- Received May 24, 2021.
- Accepted September 10, 2021.
- Copyright © 2021 by The American Association of Immunologists, Inc.
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