Fatty Acid Additive With Dexamethasone Curbs Inflammatory Signal in Cell Model

Decanoic acid, a saturated medium-chain fatty acid, suppressed the release of the proinflammatory cytokine interleukin-1β in a laboratory model of innate immune activation and, when combined with the synthetic glucocorticoid dexamethasone, allowed equivalent cytokine suppression at lower steroid concentrations. The findings come from an in vitro study using PMA-differentiated THP-1 macrophages and are reported by a research team led by Melissa A. Hausburg and David Bar-Or, with contributions from Kaysie L. Banton, Christopher D. Cassidy, Robert M. Madayag, Carlos H. Palacio, Jason S. Williams, Gregory W. Thomas, and Raphael Bar-Or.

The experimental system targeted a key step in systemic inflammatory response syndrome, a condition of excessive innate immune activation driven by trauma or infection. Dexamethasone suppresses inflammation, but adverse side effects limit its clinical use. The cells were primed overnight with lipopolysaccharide (LPS) and then stimulated with ATP for three hours in the presence of decanoic acid, dexamethasone, or both. This sequence triggers assembly of the inflammasome, a multiprotein complex that facilitates caspase-1 cleavage and the release of interleukin-1β. Under control conditions, the stimulation produced 5.56 ng/mL of interleukin-1β, with an interquartile range of 3.51 to 6.38 ng/mL. Viability and cytotoxicity were assessed, caspase-1 activity and interleukin-1β were quantified, and EC50 values were calculated by nonlinear regression.

When tested individually, both compounds inhibited interleukin-1β release. Decanoic acid showed a full dose-response EC50 of 131.7 μM, while dexamethasone was far more potent, with an EC50 of 24.29 nM. Cytotoxicity constrained the fatty acid, as decanoic acid concentrations exceeding 800 μM decreased cell viability.

To probe how the two compounds interact, the researchers used an 8-by-9 dose matrix spanning 0 to 500 μM decanoic acid and 0 to 10,000 nM dexamethasone, measuring both interleukin-1β inhibition and caspase-1 activity. The result pointed to independent action rather than synergy. Dexamethasone EC50 values remained within a narrow 95% confidence interval of 17.5 to 26.6 nM regardless of the decanoic acid background concentration, meaning the fatty acid did not shift the steroid’s potency.

The mechanistic divergence appeared in the caspase-1 measurements. Decanoic acid reduced caspase-1 enzymatic activity with a calculated EC50 of approximately 140 μM, while dexamethasone did not. This pattern indicates that the two agents act independently, with the fatty acid affecting the caspase-1 axis and the glucocorticoid operating elsewhere in the inflammatory pathway.

Because the mechanisms are distinct, their effects combined. In the co-treatment experiments, the presence of decanoic acid allowed the same degree of interleukin-1β suppression to be achieved at lower dexamethasone concentrations than the steroid required alone, a result the authors describe as supporting pharmacologic dexamethasone dose-sparing in vitro.

The dose-sparing effect is strictly a pharmacologic observation in a cell culture system. The authors state explicitly that determining whether this effect translates into clinically meaningful corticosteroid dose reduction requires further study. The LPS/ATP-stimulated THP-1 assay models one inflammasome-dependent arm of the inflammatory response, and decanoic acid’s viability effects above 800 μM narrow the concentration window in which dose-sparing could be explored. Whether the interaction holds in primary human cells, in animal models, or in clinical settings remains untested by these data.

What the results establish is a quantitative, in vitro foundation for a combination strategy: a medium-chain fatty acid that dampens caspase-1 activity and interleukin-1β release, paired with a glucocorticoid acting through an independent pathway, achieving steroid-sparing cytokine suppression without either compound altering the other’s dose-response.

Subject of Research: Pharmacologic evaluation of decanoic acid and dexamethasone co-treatment on inflammasome-driven interleukin-1β release in LPS/ATP-stimulated THP-1 macrophages

Article Title: Decanoic acid additively suppresses IL-1β and enables pharmacologic dexamethasone dose-sparing in LPS/ATP-stimulated THP-1 macrophages

Article References: Hausburg, M. A., Banton, K. L., Cassidy, C. D., Madayag, R. M., Palacio, C. H., Williams, J. S., Thomas, G. W., Bar-Or, R., & Bar-Or, D. (2026). Decanoic acid additively suppresses IL-1β and enables pharmacologic dexamethasone dose-sparing in LPS/ATP-stimulated THP-1 macrophages. PLOS One, 21(10), e0361029. https://doi.org/10.1371/journal.pone.0361029

Image Credits: AI Generated

DOI: 10.1371/journal.pone.0361029

Keywords: decanoic acid, dexamethasone, interleukin-1beta, inflammasome, caspase-1, THP-1 macrophages, LPS, ATP, glucocorticoid, dose-sparing, in vitro, systemic inflammatory response syndrome