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

Takashi Ohya; Kenichi Nishimura; Ayako Murase; Seira Hattori; Asami Ohara; Tomo Nozawa; Ryoki Hara; Shuichi Ito

doi:10.1002/acr2.11426

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

ACR Open Rheumatol. 2022 Jun;4(6):503-510. doi: 10.1002/acr2.11426. Epub 2022 Mar 11.

Authors

Takashi Ohya¹, Kenichi Nishimura¹, Ayako Murase¹, Seira Hattori¹, Asami Ohara², Tomo Nozawa¹, Ryoki Hara³, Shuichi Ito¹

Affiliations

¹ Yokohama City University, Yokohama, Kanagawa, Japan.
² Yokohama City University, Yokohama, Kanagawa and Aichi Children's Health and Medical Center, Obu, Aichi, Japan.
³ Yokohama City University and National Hospital Organization Yokohama Medical Center, Yokohama, Kanagawa, Japan.

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.

Abstract

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