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4-Octyl-Itaconate and Dimethyl Fumarate Inhibit COX2 Expression and Prostaglandin Production in Macrophages

Ciana Diskin, Alessia Zotta, Sarah E. Corcoran, Victoria J. Tyrrell, Zbigniew Zaslona, Valerie B. O’Donnell and Luke A. J. O’Neill
J Immunol November 15, 2021, 207 (10) 2561-2569; DOI: https://doi.org/10.4049/jimmunol.2100488
Ciana Diskin
*School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland; and
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Alessia Zotta
*School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland; and
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Sarah E. Corcoran
*School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland; and
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Victoria J. Tyrrell
†Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff, United Kingdom
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Zbigniew Zaslona
*School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland; and
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Valerie B. O’Donnell
†Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff, United Kingdom
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Luke A. J. O’Neill
*School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland; and
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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.

This article is featured in Top Reads, p.

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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The Journal of Immunology: 207 (10)
The Journal of Immunology
Vol. 207, Issue 10
15 Nov 2021
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4-Octyl-Itaconate and Dimethyl Fumarate Inhibit COX2 Expression and Prostaglandin Production in Macrophages
Ciana Diskin, Alessia Zotta, Sarah E. Corcoran, Victoria J. Tyrrell, Zbigniew Zaslona, Valerie B. O’Donnell, Luke A. J. O’Neill
The Journal of Immunology November 15, 2021, 207 (10) 2561-2569; DOI: 10.4049/jimmunol.2100488

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4-Octyl-Itaconate and Dimethyl Fumarate Inhibit COX2 Expression and Prostaglandin Production in Macrophages
Ciana Diskin, Alessia Zotta, Sarah E. Corcoran, Victoria J. Tyrrell, Zbigniew Zaslona, Valerie B. O’Donnell, Luke A. J. O’Neill
The Journal of Immunology November 15, 2021, 207 (10) 2561-2569; DOI: 10.4049/jimmunol.2100488
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