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Distinct roles of IL-18 and IL-1β in murine model of macrophage activation syndrome
Mao Mizuta1, Natsumi Inoue1, Masaki Shimizu2
1Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
Background:
IL-18 and IL-1β play a central role in the pathogenesis of systemic juvenile idiopathic arthritis and its life-threatening complication, macrophage activation syndrome (MAS).
Objectives:
This study aimed to clarify the role of IL-18 and IL-1β in the pathogenesis of MAS.
Methods:
We developed a mouse model to evaluate the role of each cytokine with Toll-like receptor 9 stimulation after continuous infusion with IL-18, IL-1β, and a combination of both for 7 days. The symptoms and laboratory findings were compared among the IL-18, IL-1β, and combination (IL-18+IL-1β) groups.
Results:
Body weight was significantly decreased in the IL-1β and combination groups. Splenomegaly was observed in all groups, whereas hepatomegaly was noted in the IL-18 group only. Decreased T-cell numbers, anemia, and thrombocytopenia were observed in the combination group. IFN-γ, CXCL9, and IL-12A mRNA levels were upregulated and IL-10 mRNA levels in the spleen were downregulated in the IL-18 group. Hepatomegaly and splenomegaly in the IL-18 group were observed in a dose-dependent manner. TNF-α, CXCL9, and IL-12A mRNA levels were upregulated only in those mice with extremely elevated plasma IL-18 levels.
Conclusion:
IL-18 and IL-1β have distinct roles in the pathogenesis of MAS. Dual blockade of IL-18 and IL-1β might be necessary to treat MAS.
Insights
Interleukin-18 (IL-18) and Interleukin-1β (IL-1β) have distinct roles in macrophage activation syndrome (MAS) pathogenesis. Targeting both cytokines may be crucial for effectively treating MAS.
Area of Science:
- Immunology
- Pathophysiology
Background:
- Interleukin-18 (IL-18) and Interleukin-1β (IL-1β) are key players in systemic juvenile idiopathic arthritis and its severe complication, macrophage activation syndrome (MAS).
- Understanding the specific roles of IL-18 and IL-1β is critical for developing targeted therapies.
Purpose of the Study:
- To elucidate the individual and combined roles of IL-18 and IL-1β in the pathogenesis of MAS.
- To establish a mouse model for evaluating cytokine-specific effects in MAS.
Main Methods:
- A mouse model was utilized involving continuous infusion of IL-18, IL-1β, or both for seven days, followed by Toll-like receptor 9 stimulation.
- Comparative analysis of clinical symptoms and laboratory markers across different cytokine treatment groups.
Main Results:
- IL-1β and combination groups showed significant body weight reduction.
- Hepatomegaly was specific to the IL-18 group, while splenomegaly occurred in all groups.
- The combination group exhibited decreased T-cell counts, anemia, and thrombocytopenia, alongside altered cytokine mRNA profiles.
Conclusions:
- IL-18 and IL-1β exert distinct functions in the development of MAS.
- Combined blockade of IL-18 and IL-1β may represent a promising therapeutic strategy for MAS.
