Cytokine and oxylipin production in resting and LPS-stimulated monocytes from Americans of African ancestry are influenced by ALOX5 promoter tandem repeat polymorphisms

Authors: Snodgrass, Ryan; Stephensen, Charles; ARMSTRONG, PATRICE - University Of California, Davis; ALLAYEE, HOOMAN - University Of California (UCLA); SNODGRASS, ISABEL - University Of California, Davis; Laugero, Kevin; Newman, John

Submitted to: Mediators of Inflammation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/4/2026
Publication Date: 5/15/2026
Citation: Snodgrass, R.G., Stephensen, C.B., Armstrong, P., Allayee, H., Snodgrass, I.F., Laugero, K.D., Newman, J.W. 2026. Cytokine and oxylipin production in resting and LPS-stimulated monocytes from Americans of African ancestry are influenced by ALOX5 promoter tandem repeat polymorphisms. Mediators of Inflammation. 2026(1). Article 8899139. https://doi.org/10.1155/mi/8899139.
DOI: https://doi.org/10.1155/mi/8899139

Interpretive Summary: Your body has a type of immune cell called a "monocyte". These cells are like the first responders of your immune system, and they play a big role in fighting off infections and inflammation. However, sometimes they can get a little too aggressive, and this can lead to health problems like heart disease. This study looked at a specific gene called "ALOX5" and found that people with a certain variation of this gene may be at a higher risk for heart disease. What the Study Found The researchers compared the monocytes of people with two different versions of the ALOX5 gene: The "normal" version: People with this version have monocytes that produce a good balance of inflammatory signals and anti-inflammatory molecules. The "deletion" version: People with this slightly shorter "truncated" version of the ALOX5 gene have monocytes that are more prone to inflammation. The monocytes from people with the "deletion" version of the gene showed two key differences: 1. Overactive Inflammation: These monocytes produced higher levels of inflammatory signals, such as IL-1ß and TNF-'. This means they're more likely to cause inflammation, even when there's no infection to fight. 2. Less Anti-Inflammatory Action: The monocytes from people with the "deletion" version also produced less of a molecule the researchers referred to as "TriHEPE", which exhibits structural similarity to other molecules with potent anti-inflammatory properties and helps calm inflammation. Connecting the Dots When the researchers intentionally triggered an immune response in these cells, the monocytes with the "deletion" version of the gene went into overdrive, producing even more inflammatory signals than the cells with the normal gene. They also showed signs of increased stress and damage. In simple terms, this study suggests that the "deletion" version of the ALOX5 gene makes your immune cells more inflammatory and less able to calm themselves down. This constant state of low-level inflammation provides a solid biological reason why people with this gene variation may have an increased risk of heart disease.

Technical Abstract: The ALOX5 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 remain limited. We investigated oxylipin and cytokine production in resting and LPS-stimulated CD14+ monocytes from individuals carrying promoter variants and common alleles of ALOX5. Compared to monocytes from subjects carrying two common 5 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-1ß, IL-6, TNF-', and IL-10 but lower quantities of putative trihydroxyeicosapenataenoic acid (TriHEPE) isomers detected with the same mass transition as Resolvin E1, but slightly longer retention times. With the common 55 genotype, TriHEPEs increased as IL-6, IL-10, and TNF-' production increased. This positive relationship between TriHEPEs and cytokines was diminished in monocytes with truncated ALOX5 alleles. Moreover, the d5 and dd genotypes showed enhanced IL-1ß, IL-6, and TNF-', but not IL-10, production in response to LPS. Monocytes with truncated ALOX5 promoters also produced more cyclooxygenase and 15-LOX products and showed evidence of exaggerated reactive oxygen species production. The observed changes in monocyte inflammatory mediator production provides a plausible link for the association of ALOX5 deletion alleles and CVD risk.