Abstract
Abstract: Monosodium urate (MSU) crystals are an endogenous sterile particulate that has been identified as a potent damage-associated molecular pattern (DAMP). In humans, the induction of IL-1β production through MSU-induced NLRP3 inflammasome activation in monocytes/macrophages is responsible for pathogenesis of gouty arthritis. It was recently reported that in a murine model of this disease, resveratrol decreases MSU-induced recurrent attacks of gouty arthritis. Despite its demonstrated anti-inflammatory effects, the mechanisms underlying resveratrol-mediated repression of IL-1β production in MSU-activated monocytes remain poorly understood. Here, we show that resveratrol suppresses secretion of active IL-1β by human primary monocytes stimulated with MSU crystals through suppression of Syk activation. Metabolic labeling and pull-down assays to investigate de novo protein synthesis clearly demonstrated that intracellular pro-IL-1β synthesis is rapidly repressed in monocytes after resveratrol treatment due to decreased phosphorylation of Syk and p38. Resveratrol also inhibited NLRP3 inflammasome activation in MSU-stimulated monocytes by suppressing oligomerization of ASC. Furthermore, resveratrol exerted a beneficial effect by reducing IL-1β production and inhibiting neutrophil recruitment in a mouse model of MSU-mediated peritonitis. Our findings suggest that resveratrol exerts anti-inflammatory effects via post-translational regulation of IL-1β production and, thus, may prove beneficial for the treatment of MSU crystal-mediated sterile inflammation. Key message: Resveratrol has negative effects on pro-IL-1β synthesis through Syk and p38.Resveratrol inhibits oligomerization of ASC.Resveratrol is beneficial in a mouse model of MSU-induced peritonitis.
Original language | English |
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Pages (from-to) | 369-383 |
Number of pages | 15 |
Journal | Journal of Molecular Medicine |
Volume | 97 |
Issue number | 3 |
DOIs | |
State | Published - 7 Mar 2019 |
Bibliographical note
Publisher Copyright:© 2019, Springer-Verlag GmbH Germany, part of Springer Nature.
Keywords
- Gouty arthritis
- IL-1β
- MSU
- NLRP3 inflammasome
- Resveratrol
- Syk