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

Abstract

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, r2 = 0.42; NFκB p65, r2 = 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.

Interleukin-18 cytokine in immunity, inflammation, and autoimmunity: Biological role in induction, regulation, and treatment

“…In systemic juvenile idiopathic arthritis, elevated IL-18 levels are also a hallmark of the disease. Impaired IL-18 signaling in NK cells were implicated with a dysregulated phosphorylation of the MAPK and NFkB pathways ( 194 , 195 ).…”

Pathogenic roles and diagnostic utility of interleukin-18 in autoinflammatory diseases

“…A previous report showed that NK cell dysfunction in s-JIA was closely associated with a defect in IL-18 receptor b phosphorylation (81). Furthermore, Ohya et al recently demonstrated the impaired phosphorylation of MAPK p38 and NFkB p65 in NK cells following rIL-18 stimulation in patients with active s-JIA (83). These findings indicate that IL-18 exposure might induce NK cell dysfunction and reduce the number of NK cells.…”

“…NK cell dysfunction is a characteristic finding of HLH (79) and was observed in patients with s-JIA (80)(81)(82)(83)(84). IL-18 increases NK cell activity.…”

“…IL-18 increases NK cell activity. However, exposure to high levels of IL-18 can induce NK cell death (81)(82)(83)(84). A previous report showed that NK cell dysfunction in s-JIA was closely associated with a defect in IL-18 receptor b phosphorylation (81).…”

“…Interestingly, NK cell activation was restored by IL-18 stimulation in patients with s-JIA after treatment began and serum IL-18 levels had decreased. Furthermore, Ohya et al reported that the impaired phosphorylation of MAPK p38 and NF-kB p65 in NK cells following rIL-18 stimulation was recovered to normal levels with improvements in the patients' clinical condition after treatment began (83) Recently, a case of IL-18BP deficiency with fulminant hepatitis caused by hepatitis A virus infection was reported (87). Furthermore, IL-18BPKO mice receiving repeated TLR9 stimulation developed MAS with severe hepatic inflammatory damage, which was reversed by the treatment of IL-18BP (88).…”