Tania O. Crișan 1,2, Maartje C.P. Cleophas1, Rob ter Horst1, Inge van de Munckhof1, Joost Rutten1, Tim L. Jansen3, Niels Riksen1, Charles Dinarello1,4, Mihai G. Netea1, Leo A.B. Joosten1,2
1 Department of Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands, 2 Department of Medical Genetics, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania, 3 Department of Rheumatology, VieCuri Med Centre, Venlo, The Netherlands, 4Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, USA
Background : Gout is a common metabolic disorder associated with hyperuricemia and inflammatory attacks. The levels of circulating cytokines and homeostatic molecules and their variance depending on uric acid values have seldom been described. In this study, we assessed the association between serum uric acid levels, IL-1β, IL-6, IL-8 cytokines, and plasma alpha-1-antitrysin (AAT) in gout patients, obesity with metabolic syndrome patients, and healthy volunteers.
Methods : Plasma levels of circulating cytokines IL-1β, IL-6, IL-8 was assessed using ProteinSimple array system (Biotechne). AAT was determined using a commercial ELISA kit. Uric acid was measured using common diagnostic procedures performed by the routine laboratory of Radboud UMC. All measurements were performed using EDTA plasma stored from participants in the Human functional genomics project http://www.humanfunctionalgenomics.org/site/ (healthy volunteers, 500FG; obesity, 300FG) and 240 patients diagnosed with crystal-proven gout. Spearman correlation and regression analysis were performed in R and results were considered significant at p<.05.
Results : A positive correlation has been observed between IL-1β, IL-6 and IL-8 levels over the 3 cohorts, proving their co-involvement in low grade chronic inflammation. Uric acid is positively associated to cytokine levels. Interestingly, AAT levels are negatively correlated to IL-1β levels in healthy volunteers and obese patients and also significantly associated to lower uric acid values in healthy subjects. However, this correlation is lost in the gout patient group, possibly due to AAT acting also as acute phase reactant.
Conclusions : Circulating proinflammatory cytokines show discrete variations that are measurable through highly sensitive assays and depict a general positive association to serum uric acid levels. This has been observed in gout patients, where uric acid levels typically surpass the 0.36 mM threshold, but also in obese metabolic syndrome patients and in healthy volunteers with normouricemia. A very promising finding is the negative association of AAT with plasma inflammatory cytokines and uric acid levels. This reinforces that AAT could play an important role in counterbalancing inflammation and leads to the hypothesis that uric acid could downregulate AAT levels in the blood. Future studies are warranted to assess this potential mechanistic link.
Keywords : Uric acid, circulating cytokines, alpha-1-antitrypsin