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

Diskin, Ciana, Zotta, Alessia, Corcoran, Sarah E., Tyrrell, Victoria J., Zaslona, Zbigniew, O'Donnell, Valerie B. ORCID: https://orcid.org/0000-0003-4089-8460 and O'Neill, Luke A. J. 2021. 4-Octyl-Itaconate and Dimethyl Fumarate Inhibit COX2 Expression and Prostaglandin Production in Macrophages. Journal of Immunology 207 (10) , pp. 2561-2569. 10.4049/jimmunol.2100488

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	American Association of Immunologists
ISSN:	0022-1767
Date of First Compliant Deposit:	5 January 2023
Date of Acceptance:	10 September 2021
Last Modified:	05 Jan 2023 13:53
URI:	https://orca.cardiff.ac.uk/id/eprint/149102

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