Background/Purpose

Gout is an autoinflammatory disease characterized by the deposition of monosodium urate (MSU) crystals in the joints of hyperuricaemic patients and subsequent attacks of severe gouty arthritis. Major lines of research investigating the proinflammatory effects of uric acid have been mainly focusing on MSU crystal-induced processes that come into role once uric acid reaches supersaturation. However, some indications exist that uric acid can directly have pro-inflammatory effects.  In this study we investigate the effects of high uric acid exposure on the cytokine production of primary human immune cells upon stimulation with MSU crystals and synergizing agents.

Methods

Peripheral blood mononuclear cells (PBMCs) were harvested from gout patients and healthy volunteers. Cells were pre-treated with uric acid, allantoin or left untreated for 24h and then subjected to 24h stimulation with TLR2 or TLR4 ligands in the presence or absence of MSU. Cytokine production was assessed using specific sandwich ELISA kits. mRNA levels were measured using quantitative real-time PCR.

Results

MSU crystals stimulation alone did not induce detectable levels of IL-1β or IL-6 neither in patients nor in controls, however, synergy was present between MSU and Pam3Cys or LPS. Of high importance, higher levels of IL-1β and IL-6 were seen in patients compared to controls. An enhanced pro-inflammatory cytokine production was also observed when cells were specifically pretreated with uric acid, together with a significant down regulation of IL-1Ra but not IL-10. This observation correlated with mRNA levels for these cytokines observed in uric acid pre-treated cells.

Conclusion

In this study we propose a mechanism in which high uric acid concentrations might influence inflammatory responses by facilitating IL-1β production in immune cells. We show that a mechanism for the amplification of IL-1β consists in downregulation of IL-1Ra production that has the role of counterbalancing IL-1β auto-induction loop. As a consequence, patients having hyperuricaemia could be at risk of exhibiting increased vulnerability upon encounter of acute inflammatory stimuli and this might induce enhanced states of inflammation.

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« Back to 2014 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/enhancement-of-proinflammatory-cytokine-production-by-uric-acid-in-human-cells-via-down-regulation-of-il-1ra/