Abstract
Several epidemiological studies have pointed at serum uric acid (SUA) as an independent risk factor for mortality, diabetes, hypertension, cardiovascular and kidney disease; however, no clear pathogenic pathway is established. Uric acid (UA) crystals show pro-inflammatory properties and can thus create or contribute to the state of chronic low-grade inflammation, a widely accepted pathogenic mechanism in several of the above-mentioned pathologies. On the other hand, soluble uric acid possesses antioxidant properties that might attenuate inflammatory responses. We aimed to explore the net effects of experimentally rising SUA in human whole blood cultures on several mediators of inflammation. Production of TNF-α, IL-1ß, IL-1RA, MCP-1 and IL-8 was assessed upon addition of 200 µM UA, 500 µM UA or monosodium urate (MSU) crystals in the presence or absence of 5 ng/ml lipopolysaccharide (LPS). RT-qPCR and multiplex bead based immunoassay were used to measure mRNA expression and cytokine release at 2 and 4 h of culture, respectively. 14C labeled UA was used to assess intracellular uptake of UA. We show that crystallized, but not soluble, UA induces production of pro-inflammatory mediators in human whole blood. Soluble UA is internalized in blood cells but does not potentiate or reduce LPS-induced release of cytokines.
Highlights
Epidemiological studies are conflicting whether elevated serum uric acid (SUA) is an independent risk factor for cardiovascular disease
Precipitation of uric acid into monosodium urate (MSU) crystals in joints elicits acute aseptic inflammation, the gouty arthritis, prevalence of which increases with increasing SUA levels[19]
We aimed to investigate whether short-term exposure of blood cells to high concentration of UA elicit a pro-inflammatory response or compromise cell viability, either directly or through precipitation into MSU crystals
Summary
Epidemiological studies are conflicting whether elevated serum uric acid (SUA) is an independent risk factor for cardiovascular disease. The concentration of uric acid (UA) can reach its theoretical supersaturation threshold in extracellular fluids This is due to multiple missense mutations in the uricase enzyme responsible for degrading UA to a more soluble allantoin in most other species. Anti-inflammatory effects have been reported for other antioxidants added to lipopolysaccharide (LPS)-stimulated whole blood cultures[32,33]. One doctoral thesis reported that UA attenuated inflammatory responses to LPS indirectly by inhibiting the release of pro-inflammatory cytokines TNF-α and IL-1ß in a human monocyte culture, this effect, could not be attributed to antioxidant properties of UA34. We aimed to investigate whether short-term exposure of blood cells to high concentration of UA elicit a pro-inflammatory response or compromise cell viability, either directly or through precipitation into MSU crystals. We examined to what extent UA is internalized by blood cells
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