Protective role of Oleuropein, an olive tree secoiridoid and its acyl-derivate in experimental models of rheumatic diseases

Abstract

Oleuropein (OL), an olive tree secoiridoid, and its peracetylated derivate (Per-OL) have exhibited several beneficial effects reducing acute inflammatory responses on LPS-stimulated macrophages. The present study was designed to evaluate the effects of both dietary OL and Per-OL supplementations on collagen-induced arthritis (CIA) murine model. Three-weeks-old DBA-1/J male mice were fed from weaning with 0.05% (w/w) OL, 0.05% or 0.025% Per-OL. After six weeks of pre-treatment, arthritis was induced by bovine collagen type II by tail base injection (day 0) and mice received a booster injection on day 21. Mice were sacrificed 42 days after first immunization. Then, blood was recollected and paws were histological and biochemically processed. OL and Per-OL experimental diets significantly prevented histological damage and arthritic score development in RA. In addition, serum collagen oligomeric matrix protein (COMP) and metalloproteinase 3 (MMP)-3 as well as proinflammatory cytokines levels in paw homogenates (including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-17 and interferon (IFN)-γ were significantly ameliorated in those animals fed with dietary secoiridoids. Mitogen-activated protein kinases (MAPKs) and nuclear transcription factor kappa-B (NF-κB) activations were drastically down-regulated whereas nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) protein expressions were significantly up-regulated in those mice fed with OL and Per-OL diets. These results reveal, for the first time, the anti-inflammatory effect of a diet supplemented with OL and Per-OL in an experimental murine model of CIA, which was accompanied by a significant reduction in the pro-inflammatory markers studied (COMP, MMP-3, TNF-α, IL-1β, IL-6, IL-17 and IFN-γ). The mechanisms involved could be related to an activation of the antioxidant pathway Nrf2/HO-1 and an inhibition of MAP kinases and NF-κB signaling pathways activations. On the other hand, we studied the effects of both OL and Per-OL diets supplemented diets in a model of pristane-induced systemic lupus erythematosus (SLE) in BALB / c mice. Mice received an intraperitoneal injection of pristane or saline according to the experimental groups and were fed with experimental diets enriched with OL and Per-OL. Changes in cytokines levels and pro-inflammatory markers were evaluated by the ELISA assay. Changes in the protein expression of inducible nitric oxide synthase (iNOS), microsomal prostaglandin E synthase 1 (mPGEs-1) as well as HO-1, nuclear factor Nrf2, p38 protein kinases, C-jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), signal transduction factor and activator of transcription (STAT) -3, NF-κB and inflammasome NLRP3 activation were determined using the Western Blot. Both OL and Per-OL dietary treatments significantly reduced kidney damage and reduced serum MMP-3 and renal prostaglandin E2 (PGE2) levels. Our studies indicated that OL and Per-OL enriched diets produced an increase in the expression of the antioxidant pathway Nrf2 / HO-1 which was accompanied by a decrease in the activation of the Janus kinases and signal transducer and activator of transcription (JAK / STAT), MAPKs, NF-κB and inflammasome NLRP3 proteins. In conclusion, dietary supplementation with OL and Per-OL could serve as the basis for the development of new nutritional strategies for the prevention of RA. In addition, these results also suggest that dietary supplementation with OL and Per-OL could constitute a new alternative therapeutic approach as a preventive or palliative of nephritis in the management of SLE.