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Objective  Systemic juvenile idiopathic arthritis (sJIA) is characterized by fever, arthritis, rash, hepatosplenomegaly, and macrophage activation syndrome; however, its pathogenesis is still unclear. Elevated serum interleukin (IL)‐18 concentrations and decreased natural killer (NK) cell activity are characteristic of active disease; thus, we examined IL‐18 signaling in NK cells from sJIA.    Methods  We analyzed mitogen‐activated protein kinase (MAPK) p38 and nuclear factor κ light chain enhancer of activated B cells (NFκB) p65 phosphorylation in NK cells after in vitro recombinant IL‐18 (rIL‐18) stimulation in 31 patients with sJIA. Associations between clinical features, serum IL‐18, and phosphorylation intensity were analyzed. Furthermore, we investigated the effects of high IL‐18 concentrations on phosphorylation in NK cells.    Results  Patients were divided according to their disease activity: systemic features (n = 8), chronic arthritis (n = 7), remission on medication (n = 10), and remission off medication (n = 6). MAPK p38 and NFκB p65 phosphorylation intensity were the highest in healthy controls, followed by remission off medication, remission on medication (vs. control; MAPK p38,  P  < 0.01; NFκB p65,  P  < 0.05), chronic arthritis ( P  < 0.001,  P  < 0.001), and systemic features ( P  < 0.001,  P  < 0.001). The systemic features group showed a complete defect in phosphorylation. Serum IL‐18 was the highest in the systemic features group followed by chronic arthritis, remission on medication ( P  < 0.01), remission off medication ( P  < 0.01), and healthy controls ( P  < 0.01). Phosphorylation intensity was negatively correlated with serum IL‐18 (MAPK p38,  r  2  = 0.42; NFκB p65,  r  2  = 0.54). Furthermore, healthy control NK cells were cultured with rIL‐18; impaired phosphorylation was reproduced in vitro.    Conclusion  Impaired IL‐18 signaling in NK cells correlated with disease activity in sJIA. High serum IL‐18 exposure induces impaired MAPK and NFκB phosphorylation in NK cells.

Impaired Interleukin‐18 Signaling in Natural Killer Cells From Patients With Systemic Juvenile Idiopathic Arthritis