Modulatory effect of fenofibrate on endothelial production of neutrophil chemokines IL-8 and ENA-78.

Purpose: The PPAR-alpha agonists (fibrates) are commonly used in the treatment of dyslipidemia. It has been hypothesized that the cardio-protective effects of fibrates are partially due to immunomodulatory effects. However, there is a paucity of data regarding the effect of fibrates on neutrophilic chemokines such as epithelial neutrophil activating protein (ENA-78) and interleukin (IL)-8. We investigated the influence of fenofibrate on IL-1β-stimulated production of ENA-78 and IL-8 from human endothelial cells (HUVECs).

Methods: HUVECs were cultured in the presence or absence of IL-1β and fenofibrate ranging from 1-50 uM. ENA-78 and IL-8 were measured and normalized to total protein content in cell culture supernates by multiplex immunofluorescence detection. Experimental samples were measured in triplicate. Significance was set at P < 0.05 by ANOVA with correction for multiple comparisons.

Results: Endothelial production of both ENA-78 and IL-8 was induced by the proinflammatory cytokine IL-1β. ENA-78 concentrations increased by more than 160-fold over constitutively produced ENA-78 upon IL-1β stimulation (mean ± SEM: 10,129 ± 1591 pg/mg vs. 61 ± 9.5 mg/mg; P < 0.0001). IL-8 concentrations increased by slightly over 5-fold (6145 ± 860 pg/mg vs. 1160 ± 201 pg/mg; P = 0.0003). ENA-78 protein and mRNA were significantly reduced by fenofibrate while no drug effects were observed on IL-8 production.

Conclusions: Fenofibrate blunts IL-1β-mediated ENA-78 production with no effect on IL-8. This represents a novel mechanism by which fenofibrate exerts anti-inflammatory effects and should be further explored.