The electrophilic 17-oxo-docosahexaenoic acid (17-oxo-DHA) enhances the anti-inflammatory potency of fluticasone propionate

Abstract

The electrophilic cyclooxygenase-2-derived 17-oxo-DHA promotes anti-oxidant and anti-inflammatory effects by acting through Nrf2-dependent and -independent mechanisms. Herein we investigated the anti-inflammatory efficacy of 17-oxo-DHA compared with fluticasone propionate (FP). In LPS-stimulated human macrophages, 17-oxo-DHA and FP displayed a similar pattern of cytokine suppression, with additive effects for TNFα, IL-6, IL-12, RANTES. In addition, 17-oxo-DHA suppressed two cytokines that were insensitive to FP (IL-1β and C-GSF) thus displaying a broader spectrum of activity compared to the steroid. These data indicated that (i) 17-oxo-DHA and FP act through complementary and synergistic mechanisms and (ii) the combination of the two drugs results in increased anti-inflammatory potency. To assess whether 17-oxo-DHA was able to overcome steroid resistance, THP1 cells were stimulated with IL-1β/10% cigarette smoke extract (CSE) and TNFα suppression by FP was measured. In this experimental model, the efficacy and potency of FP in suppressing TNFα (measured as IC 50 and I max ) were significantly reduced compared to LPS-stimulated cells. The addition of 17-oxo-DHA led to a significant increase of FP potency both in LPS- and IL-1β/CSE-stimulated cells (I max 98.5% and 97.7%, respectively), without changes of the IC 50 . These data suggest that 17-oxo-DHA did not revert the steroid resistant phenotype but significantly enhanced the potency of FP, also in the presence of IL-1β/CSE, with mechanisms to be defined. Overall, data herein reported support that 17-oxo-DHA enhances the anti-inflammatory potency of FP and may be useful to overcome steroid resistance.