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

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Abstract
Systemic inflammatory response syndrome, driven by trauma or infection, involves excessive innate immune activation. Dexamethasone (DEX), a synthetic glucocorticoid, suppresses inflammation, although adverse side effects limit its clinical use. The inflammasome, a multiprotein complex that assembles in response to inflammatory stimuli like ATP after lipopolysaccharide (LPS) priming, facilitates caspase-1 cleavage and release of the proinflammatory cytokine, interleukin (IL)-1β. We investigated whether DEX and decanoic acid (DA), a saturated medium-chain fatty acid, inhibited caspase-1 activity and IL-1β release in an LPS/ATP-stimulated THP-1 macrophage model and whether co-treatment would allow for pharmacologic DEX dose-sparing in vitro. PMA-differentiated THP-1macrophages were primed with LPS overnight and stimulated with ATP for 3 h in the presence of DA, DEX, or both. Viability and cytotoxicity were assessed. Caspase-1 activity and IL-1β were quantified, and EC 50 values were calculated by nonlinear regression. In control conditions, LPS/ATP stimulation induced 5.56 (q1: 3.51 – q3: 6.38) ng/mL of IL-1β release. DA and DEX inhibited IL-1β with full dose-response EC 50 values of 131.7 μM and 24.29 nM, respectively. DA concentrations exceeding 800 μM decreased cell viability. An 8 x 9-point DA/DEX dose matrix (0–500 μM DA; 0 to 1e4 nM DEX) was used to interrogate drug interaction for IL-1β inhibition and caspase-1 activity. DEX EC 50 values remained within a narrow 95% confidence interval of 17.5–26.6 nM, regardless of DA background concentration. DA reduced caspase-1 enzymatic activity with a calculated EC 50 value of ~140 μM; whereas, DEX did not. These data show that DA and DEX act independently. Furthermore, compared to DEX alone, the presence of DA allowed for equivalent in vitro IL-1β suppression at lower DEX concentrations, supporting pharmacologic DEX dose-sparing. Determination of whether this pharmacologic effect translates to clinically meaningful corticosteroid dose reduction requires further study.
Funding Information
  • Swedish Medical Center, Wesley Medical Center, and McAllen Medical Center, and Intermountain Health affiliated, Lutheran Medical Center
  • Swedish Medical Center, Wesley Medical Center, and McAllen Medical Center, and Intermountain Health affiliated, Lutheran Medical Center
  • Swedish Medical Center, Wesley Medical Center, and McAllen Medical Center, and Intermountain Health affiliated, Lutheran Medical Center
  • Swedish Medical Center, Wesley Medical Center, and McAllen Medical Center, and Intermountain Health affiliated, Lutheran Medical Center
  • Swedish Medical Center, Wesley Medical Center, and McAllen Medical Center, and Intermountain Health affiliated, Lutheran Medical Center
  • Swedish Medical Center, Wesley Medical Center, and McAllen Medical Center, and Intermountain Health affiliated, Lutheran Medical Center
  • Swedish Medical Center, Wesley Medical Center, and McAllen Medical Center, and Intermountain Health affiliated, Lutheran Medical Center
  • Swedish Medical Center, Wesley Medical Center, and McAllen Medical Center, and Intermountain Health affiliated, Lutheran Medical Center
  • Swedish Medical Center, Wesley Medical Center, and McAllen Medical Center, and Intermountain Health affiliated, Lutheran Medical Center
  • Insignia Pharmaceuticals, LLC

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