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Interleukin-33/ST2 Axis as Potential Biomarker and Therapeutic Target in Kawasaki Disease

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Abstract—

Kawasaki disease (KD) is an acute, self-limiting, febrile systemic vasculitis of unknown cause associated with the development of coronary artery lesions (CALs) during childhood. Damage-associated molecular patterns (DAMPs) from cell death and oxidative stress have been shown to be involved in the development of KD vasculitis. Interleukin (IL)-33 is released from damaged endothelial cells and acts as a DAMP. We studied whether IL-33 and its receptor (ST2) might be involved in KD pathogenesis. Serum levels of soluble ST2 (sST2) in KD patients were measured before their first therapy. Furthermore, we investigated the impact of IL-33 on human coronary artery endothelial cells (HCAECs). Serum levels of sST2 were significantly higher in KD patients with CALs than in those with normal coronary arteries. In vitro, IL-33 upregulated the expression of ST2L and increased production of sST2, IL-6, IL-8, and monocyte chemoattractant protein−1 in HCAECs in a time- and concentration-dependent manner. Moreover, IL-33 induced significantly greater production of IL-6 and IL-8 in HCAECs compared to the condition stimulated with isoconcentration of tumor necrosis factor-α. The results of the present study suggest that the IL-33/ST2 axis might be involved in the development of KD vasculitis. The IL-33/ST2 axis may be a therapeutic target for the treatment of KD.

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Funding

This work was supported by JSPS KAKENHI (Grant number, JP21K15906) (S.O.), AMED (Grant number, JP22ek0109606) (S.O.), and a grant from Japan Blood Products Organization and partially supported by Inokuma Prize.

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  1. Department of Pediatrics, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, Japan

    Seigo Okada, Hiroki Yasudo, Yuji Ohnishi, Chie Matsuguma, Reiji Fukano, Takahiro Motonaga, Takako Waniishi & Shunji Hasegawa

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Contributions

Seigo Okada contributed to conception, design, acquisition, analysis, and interpretation of data, and drafting the article. Hiroki Yasudo contributed to conception, design, and interpretation of data. Yuji Ohnishi contributed to design, acquisition, analysis, and interpretation of data. Chie Matsuguma, Takahiro Motonaga, and Takako Waniishi contributed to acquisition and analysis of data. Reiji Fukano contributed to analysis and interpretation of data. Shunji Hasegawa contributed to revising it critically for important intellectual content and final approval of the version to be published. The first draft of the manuscript was written by Seigo Okada and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Yamaguchi University Hospital Institutional Review Board (Date 27/06/2016/No. H28-047).

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Okada, S., Yasudo, H., Ohnishi, Y. et al. Interleukin-33/ST2 Axis as Potential Biomarker and Therapeutic Target in Kawasaki Disease. Inflammation 46, 480–490 (2023). https://doi.org/10.1007/s10753-022-01753-7

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