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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. 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 Acceptance: 10 September 2021
Last Modified: 12 Apr 2022 10:14
URI: https://orca.cardiff.ac.uk/id/eprint/149102

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