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

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 TNF?, IL-6, IL-12, RANTES. In addition, 17-oxo-DHA suppressed two cytokines that were insensitive to FP (IL-1? 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-1?/10% cigarette smoke extract (CSE) and TNF? suppression by FP was measured. In this experimental model, the efficacy and potency of FP in suppressing TNF? (measured as IC50 and Imax) 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-1?/CSE-stimulated cells (Imax 98.5% and 97.7%, respectively), without changes of the IC50. 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-1?/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.