The role and impact of the IL-6 mediated JAK2-STAT1/3 signaling pathway in the pathogenesis of gout

Zeng Zhang ^1,2 Peng Wang ¹ Tianyi Lei ¹ Jianwei Guo ¹ Yi Jiang ¹ Yanhui Li ¹ Jianxiong Zheng ¹ Shunbing Wang ¹ Haimuzi Xu ¹ Guilin Jian ^1,2 Quanbo Zhang ^1* Yu-Feng Qing ^1*

• ¹ Affiliated Hospital of North Sichuan Medical College, Nanchong, China
• ² Suining Third People's Hospital, Suining, China

IL-6 is a pleiotropic cytokine. the role and impact of IL-6 as an upstream regulator of the JAK2-STAT1/3 pathway in gout have seldom been reported. This study explores the influence and role of upstream IL-6 in regulating the JAK2-STAT1/3 signaling pathway on gout inflammation, offering new insights for targeted therapeutic interventions and drug development in gout management.Methods and Results: Clinical data and peripheral blood specimens were collected from gout patients and healthy individuals. In vitro and in vivo models of acute gout inflammation were established by stimulating PBMCs, THP-1 cells, and mice with MSU crystals. IL-6 expression was manipulated using IL-6 agonists and KO mouse technology to investigate the role and impact of the IL-6-mediated JAK2-STAT1/3 signaling pathway in gout models. Serum IL-6 protein expression levels were significantly elevated in patients with GA compared to healthy individuals, with multifactor logistic regression revealing an OR of 2.175 for IL-6. In GA patients, mRNA expression of IL-6, JAK2, STAT1/3, and IL-1β was notably lower in the gout group compared to the HC group. Moreover, IL-6, JAK2, STAT1/3, p-JAK2, p-STAT1/3, and IL-1β proteins were markedly higher in the AG group compared to the IG and HC groups. Within the IG group, IL-6, JAK2, STAT3, and IL-1β proteins were significantly elevated compared to the HC group, whereas STAT1, p-JAK2, and p-STAT1/3 proteins were significantly lower. The expression of IL-6 protein and JAK2 mRNA showed positive correlations with certain inflammatory markers. In the acute gout THP-1 cell model, The 6-hour model group showed significantly higher levels of IL-1β, IL-6, JAK2, STAT1/3 mRNA, and corresponding proteins, including their phosphorylated forms, compared to the blank control group. Additionally, treatment with an IL-6 agonist further increased these expression levels compared to the untreated model group. In the acute gout mouse model, IL-6 KO mice exhibited significantly reduced footpad swelling and swelling index compared to WT mice. IL-6 emerges as a potential risk factor for acute gout attacks, with its involvement in the JAK2-STAT1/3 signaling pathway contributing to the inflammation and pathogenesis process of acute gout through positive feedback mechanisms.