Session Type: Abstract Submissions (ACR)
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. It is known for centuries that the MSU crystals are the necessary causative agent of gout but, in addition, it is now proven that MSU requires synergizing stimuli to induce high cytokine responses, relevant for the clinical picture of gout. Here we investigate the inflammatory response in gout patients and healthy controls upon stimulation with MSU crystals in combination with other ligands. We also investigate the effects of elevated uric acid concentrations on the pro-inflammatory cytokine production in human immune cells.
Peripheral blood mononuclear cells (PBMCs) were harvested from patients diagnosed with crystal-proven gout and from age matched healthy volunteers. Cells were stimulated for 24 hours with Pam3Cys or palmitic acid (C16) in the presence or absence of MSU crystals. In separate experiments, the cells were first treated with uric acid or left untreated for 24h and then subjected to stimulation with Pam3Cys or LPS for another 24h. Production of IL-1beta, IL-6 was assessed using specific sandwich ELISA kits. mRNA levels were measured using quantitative real time PCR. Differences were assessed using the Mann-Whitney test and a p-value<0.05 was considered statistically significant.
MSU crystals stimulation alone did not induce detectable levels of IL-1β or IL-6 neither in patients nor in controls, however, a significant synergy between MSU and Pam3Cys or C16 was observed. Of high importance, significantly higher levels of IL-1β and IL-6 were observed in patients compared to controls. Subsequently, when cells were pretreated with uric acid, an enhanced cytokine production was observed in cells stimulated with Pam3Cys or LPS in the presence or absence of MSU, however, uric acid alone did not induce this effect. This enhanced cytokine production correlated with higher mRNA levels observed in uric acid pre-treated cells.
Enhanced cytokine production was observed in cells originating from gout patients compared to controls when stimulated with MSU crystals and synergizing stimuli. Similar trends could be identified when the cells were pre-treated with high uric acid levels in vitro and then subjected to MSU crystals stimulation. These results indicate that high uric acid levels could have an effect on immune cells and facilitate higher responses upon encounter of inflammatory stimuli and this could be a mechanism for the enhanced pro-inflammatory response observed in gout patients.
T. O. Crisan,
M. G. Netea,
T. L. Jansen,
L. A. Joosten,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/enhanced-il-1%ce%b2-and-il-6-production-in-gout-patients-upon-stimulation-with-mono-sodium-urate-crystals-and-synergizing-agents-compared-to-healthy-volunteers/