Mediators Inflamm. 2026;2026(1):e8899139. doi: 10.1155/mi/8899139.
ABSTRACT
The arachidonate 5-lipoxygenase (ALOX5) specificity protein 1 (Sp1) promoter tandem repeat polymorphism is associated with enhanced cardiovascular disease (CVD) risk. However, a functional understanding of these variants in immune cells central to disease development remains limited. We investigated oxylipin and cytokine production in resting and lipopolysaccharide (LPS)-stimulated CD14+ monocytes from individuals carrying promoter variants and common alleles of ALOX5. Compared to monocytes from subjects carrying two common five-repeat alleles (55 genotype), resting monocytes from individuals carrying one or more ALOX5 deletion (d) alleles (d5 and dd genotypes) produced increased levels of IL-1β, IL-6, TNF-ɑ, and IL-10 but lower quantities of putative trihydroxyeicosapenataenoic acid (TriHEPE) isomers detected with the same mass transition as resolvin E1 (RvE1) but slightly longer retention times. With the common 55 genotype, TriHEPEs increased as IL-6, IL-10, and TNF-ɑ production increased. This positive relationship between TriHEPEs and cytokines was diminished in monocytes with truncated ALOX5 alleles. In response to LPS, monocytes from individuals with d5 and dd genotypes produced higher levels of IL-1β, IL-6, and TNF-ɑ but not IL-10, as well as increased quantities of cyclooxygenase (COX) products 11-hydroxyeicosatetraenoic acid (11-HETE), prostaglandin E2 (PGE), thromboxane B (TxB), prostaglandin F2α (PGF), prostaglandin E1 (PGE), and prostaglandin B2 (PGB) compared to monocytes from individuals with the common 55 genotype. The observed changes in monocyte inflammatory mediator production provide a plausible link for the association of ALOX5 deletion alleles and CVD risk. Trial Registration: Clinical trial: registered on ClinicalTrials.gov (Identifier: NCT00536185).
PMID:42141771 | DOI:10.1155/mi/8899139