Regulation of SOCS3-STAT3 in urate-induced cytokine production in human myeloid cells

Objective. - Hyperuricaemia is necessary for gout. High urate concentrations have been linked to inflammation in mononuclear cells. Here, we explore the role of the suppressor of cytokine signaling 3 (SOCS3) in urate-induced inflammation. Methods. - Peripheral blood mononuclear cells (PBMCs) from gout patients, hyperuricemic and normouricemic individuals were cultured for 24 h with varying concentrations of soluble urate, followed by 24 h restimulation with lipopolysaccharides (LPS) +/- monosodium urate (MSU) crystals. Transcriptomic profiling was performed using RNA-Sequencing. DNA methylation was assessed using Illumina Infinium (R) MethylationEPIC BeadChip system (EPIC array). Phosphorylation of signal transducer and activator of transcription 3 (STAT3) was determined by flow cytometry. Cytokine responses were also assessed in PBMCs from patients withJAK2 V617F tyrosine kinase mutation. Results. - PBMCs pre-treated with urate produced more interleukin-1beta (IL-1S) and interleukin-6 (IL6) and less interleukin-1 receptor anatagonist (IL-1Ra) after LPS simulation. In vitro, urate treatment enhanced SOCS3 expression in control monocytes but no DNA methylation changes were observed at the SOCS3 gene. A dose-dependent reduction in phosphorylated STAT3 concomitant with a decrease in IL-1Ra was observed with increasing concentrations of urate. PBMCs with constitutively activated STAT3 (JAK2 V617F mutation) could not be primed by urate. Conclusion. - In vitro, urate exposure increased SOCS3 expression, while urate priming, and subsequent stimulation resulted in decreased STAT3 phosphorylation and IL-1Ra production. There was no evidence that DNA methylation constitutes a regulatory mechanism of SOCS3. Elevated SOCS3 and reduced pSTAT3 could play a role in urate-induced hyperinflammation since urate priming had no effect in PBMCs from patients with constitutively activated STAT3. (c) 2024 L'Auteur(s). Publie ' par Elsevier Masson SAS au nom de Socie ' te ' franc,aise de rhumatologie. Cet article est publie ' en Open Access sous licence CC BY (http://creativecommons.org/licenses/by/4.0/).