Abstract
IntroductionMonosodium urate monohydrate (MSU) crystals synergize with various toll-like receptor (TLR) ligands to induce cytokine production via activation of the NOD-like receptor (NLR) family, pyrin domain-containing 3 (NLPR3) inflammasome. This has been demonstrated in vitro using human cell lines or monocytes of healthy volunteers. In the present study, we have investigated the effect of MSU crystals and of their combination with TLR ligands in peripheral blood mononuclear cells (PBMC) of patients with gout.MethodsPBMCs from 18 patients with primary gout and 12 healthy donors were exposed to MSU crystals in the presence or absence of saturated fatty acid C18:0 (free fatty acid, TLR2 ligand), palmitoyl-3-cystein (Pam3Cys, TLR1/2 ligand) and fibroblast stimulating factor-1 (FSL-1, TLR 2/6 ligand). Production of IL-1β, IL-6, IL-8, IL-17 and tumor necrosis factor alpha (TNFα) was determined by ELISA. mRNA transcripts of IL-1β were measured by real-time PCR.ResultsMSU crystals alone failed to induce IL-1β, IL-6 or TNFα in both patients and control groups, but a stronger synergy between MSU/Pam3Cys and MSU/C18:0 for the induction of IL-1β was found in patients with gout compared to healthy controls. IL-6, but not IL-8, followed the kinetics of IL-1β. No production of the neutrophil-recruiting IL-17 was detectable after stimulation of the patients' PBMCs with MSU in both the presence or absence of TLR ligands. No change of gene transcripts of IL-1β after stimulation with MSU and Pam3Cys or with MSU and C18:0 was found. A positive correlation was found between synergy in IL-1β production from PBMCs of patients between C18:0 and MSU crystals, as well as the annual number of attacks of acute gouty arthritis (rs: +0.649, P: 0.022).ConclusionsThe synergy between MSU crystals and TLR-2 ligands is more prominent in patients with gout than in controls. This is likely mediated by the enhanced maturation of pro-IL-1β into IL-1β.
Highlights
Monosodium urate monohydrate (MSU) crystals synergize with various toll-like receptor (TLR) ligands to induce cytokine production via activation of the NOD-like receptor (NLR) family, pyrin domain-containing 3 (NLPR3) inflammasome
We found that production of IL-1b did not significantly differ between patients and controls, IL-1b production in cells of gout patients showed a wide variation and a tendency to higher production when exposed to Pam3Cys (Figure 2A)
When peripheral blood mononuclear cells (PBMCs) of gout patients were incubated with monosodium urate monohydrate (MSU) crystals together with Pam3Cys, production of IL-1b was significantly increased compared to Pam3Cys alone (Figure 4)
Summary
Monosodium urate monohydrate (MSU) crystals synergize with various toll-like receptor (TLR) ligands to induce cytokine production via activation of the NOD-like receptor (NLR) family, pyrin domain-containing 3 (NLPR3) inflammasome. This has been demonstrated in vitro using human cell lines or monocytes of healthy volunteers. The arthritis is mediated by pro-inflammatory cytokines, produced by activated innate immune cells [2] Among these cytokines, IL-1b seems to play a pivotal role [3]. MSU crystals have been reported to activate the MOD-like receptor (NLR) family, pyrin domain-containing 3 (NLPR3) inflammasome and induce IL-1b production via caspase-1dependent processing [9,10]. Purified MSU crystals induce moderate amounts of IL-1b by themselves [11,12]; they require co-stimulation with toll-like receptor (TLR) ligands such as lipopolysaccharide (LPS) [11] or free fatty acids (FFA) [12]
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