Oxyresveratrol Inhibits R848-Induced Pro-Inflammatory Mediators Release by Human Dendritic Cells Even When Embedded in PLGA Nanoparticles

Abstract

Oxyresveratrol, a stilbene extracted from the plant Artocarpus lakoocha Roxb., has been reported to provide a considerable anti-inflammatory activity. Since the mechanisms of this therapeutic action have been poorly clarified, we investigated whether oxyresveratrol affects the release of the pro-inflammatory cytokines IL-12, IL-6, and TNF-α by human dendritic cells (DCs). We found that oxyresveratrol did not elicit per se the release of these cytokines, but inhibited their secretion induced upon DC stimulation with R848 (Resiquimod), a well-known immune cell activator engaging receptors recognizing RNA viruses. We then investigated whether the inclusion of oxyresveratrol into nanoparticles promoting its ingestion by DCs could favor its effects on cytokine release. For this purpose we synthesized and characterized poly(lactic-co-glycolic acid) (PLGA) nanoparticles, and we assessed their effects on DCs. We found that bare PLGA nanoparticles did not affect cytokine secretion by resting DCs, but increased IL-12, IL-6, and TNF-α secretion by R848-stimulated DCs, an event known as “priming effect”. We then loaded PLGA nanoparticles with oxyresveratrol and we observed that oxyresveratrol-bearing particles did not stimulate the cytokine release by resting DCs and inhibited the PLGA-dependent enhancement of IL-12, IL-6, and TNF-α secretion by R848-stimulated DCs. The results herein reported indicate that oxyresveratrol suppresses the cytokine production by activated DCs, thus representing a good anti-inflammatory and immune-suppressive agent. Moreover, its inclusion into PLGA nanoparticles mitigates the pro-inflammatory effects due to cooperation between nanoparticles and R848 in cytokine release. Therefore, oxyresveratrol can be able to contrast the synergistic effects of nanoparticles with microorganisms that could be present in the patient tissues, therefore overcoming a condition unfavorable to the use of some nanoparticles in biological systems.

Oxyresveratrol-Loaded PLGA Nanoparticles Inhibit Oxygen Free Radical Production by Human Monocytes: Role in Nanoparticle Biocompatibility

“…Empty (PLGA) and oxyresveratrol-loaded PLGA nanoparticles (PLGA–Oxy) have been prepared following a previously used protocol [ 38 ]: Therefore, particle size and ζ-potential were completely comparable to those previously published by our group. To investigate the uptake of PLGA nanoparticles by monocytes we prepared fluorescence-responsive rhodamine B-loaded PLGA nanoparticles (PLGA–Rhod).…”

“…The PLGA nanoparticles embedded with oxyresveratrol used in this study were prepared as previously described [ 38 ]. Briefly, 10 mg of the 50:50 lactide–glycolide ratio PLGA polymer and 5 mM (1.22 mg) of oxyresveratrol were co-dissolved in 1 mL of organic solvent (95% acetone and 5% DMSO); the obtained organic phase was added dropwise under stirring (2000 RPM) to 10 mL of 1% polyvinyl alcohol (PVA) aqueous solution and left overnight to evaporate the organic phase.…”

Effects of Magnetic Nanoparticles on the Functional Activity of Human Monocytes and Dendritic Cells

“…Additionally, porous silicon-TiO 2 microparticles increased the LPS-induced IL-12 and TNF-α secretion by human DCs [ 44 ]. Moreover, PLGA nanoparticles increased IL-12, TNFα, and IL-6 secretion by R848-stimulated DCs [ 45 ] and enhanced β-glucan-induced O 2 − production in human monocytes [ 18 ]. Therefore our finding that both MNPs and BMNPs did not cooperate with three stimuli such as β-glucan [ 66 , 67 ], R848 [ 51 ], and LPS [ 50 , 56 ], that mimic the natural interaction between immune cells and pathogenic fungi, viruses, and bacteria, as well as with PMA, a molecule structurally related to the natural NOX2 NADPH oxidase activator diacylglycerol [ 68 , 69 ] suggests that both magnetic nanoparticles could be good candidates for medical applications.…”

“…Briefly, monocytes were treated with 50, 150, or 300 μg/mL MNPs or BMNPs as well as with 100 ng/mL LPS or 5 μM R848 (InvivoGen, San Diego, CA, USA) alone or in combination with MNPs or BMNPs. After 18 h, the supernatants were collected and processed as previously described [ 45 ].…”

“…Finally, a nanoparticle unable to activate immune cells and, therefore, generally considered biocompatible, could instead enhance the pro-inflammatory effect of some microorganisms or their derivatives [ 18 , 43 , 44 , 45 ] through a cooperative event named “cell priming” [ 46 , 47 ]. This implies that, if this apparently harmless nanoparticle is administered to the patient in the presence of other agents such as pathogenic fungi, bacteria, or viruses, it might cause unwanted dangerous effects as it can induce a hyper-responsiveness of leukocytes to the above-mentioned agents.…”