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Interleukin-33/ST2 signaling contributes to the severity of hemolytic uremic syndrome induced by enterohemorrhagic Escherichia coli

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Abstract

Objectives

Interleukin (IL)-33 plays an important role in host defense, immune regulation, and inflammation. This study assessed IL-33’s role in the pathogenesis of severe hemolytic uremic syndrome (HUS) induced by enterohemorrhagic Escherichia coli (EHEC). We also investigated the clinical significance of IL-33 and soluble ST2 (soluble form of IL-33 receptor) serum levels in patients with EHEC-induced HUS.

Methods

The role of IL-33 in Shiga toxin (STx)-2-induced endothelial injury was studied in human umbilical vein endothelial cells (HUVECs) in vitro. Blood samples were obtained from 21 HUS patients and 15 healthy controls (HC). The IL-33 and sST2 serum levels were quantified using an enzyme-linked immunosorbent assay. The results were compared to HUS’ clinical features.

Results

Cytotoxic assays indicated that IL-33 enhanced STx2 toxicity in HUVECs. Serum IL-33 levels in most HUS patients were below the lowest detection limit. On the other hand, serum sST2 levels in patients during the HUS phase were significantly higher than those in HC and showed a correlation with disease severity. Serum sST2 levels in patients with encephalopathy were significantly higher than those in patients without it. A serum sST2 level > 63.2 pg/mL was associated with a high risk of encephalopathy. Serum sST2 levels significantly correlated with serum levels of inflammatory cytokines related to the development of HUS.

Conclusions

Our results indicate that IL-33 contributes to the severity of EHEC-induced HUS. Serum sST2 level in HUS patients correlated with disease activity, which suggests its potential role as a marker for disease activity and development of encephalopathy in patients with EHEC-induced HUS.

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Acknowledgements

The authors thank Dr. Michio Konishi, Department of Pediatrics, Tonami General Hospital, Tonami; Dr. Noboru Igarashi, Department of Pediatrics, Toyama Prefectural Central Hospital, Toyama; Dr. Junya Yamahana, Division of Nephrology, Toyama Prefectural Central Hospital, Toyama; Dr. Hiromichi Taneichi and Dr. Hirokazu Kanegane, Department of Pediatrics, Graduate School of Medicine, University of Toyama, Toyama; Dr. Mika Ito and Dr. Shigeru Saito, Department of Obstetrics and Gynecology, University of Toyama; Dr. Kengo Furuichi and Dr. Takashi Wada, Division of Nephrology, Kanazawa University Hospital, Kanazawa, Japan; and Dr. Masaru Nakagawa and Dr. Hitoshi Yokoyama, Department of Nephrology, Kanazawa Medical University, Kahoku-gun, for the clinical support and for collecting the data and clinical samples for this study.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors have no financial relationship to this article to disclose.

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Authors and Affiliations

  1. Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8641, Japan

    Shimpei Yamada, Masaki Shimizu, Mondo Kuroda, Natsumi Inoue & Akihiro Yachie

  2. Department of Physiology, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, 920-8641, Japan

    Naotoshi Sugimoto

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  1. Shimpei Yamada
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  2. Masaki Shimizu
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  3. Mondo Kuroda
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  4. Natsumi Inoue
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  5. Naotoshi Sugimoto
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  6. Akihiro Yachie
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Correspondence to Masaki Shimizu.

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The authors declare that they have no competing interest.

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Yamada, S., Shimizu, M., Kuroda, M. et al. Interleukin-33/ST2 signaling contributes to the severity of hemolytic uremic syndrome induced by enterohemorrhagic Escherichia coli. Clin Exp Nephrol 23, 544–550 (2019). https://doi.org/10.1007/s10157-018-1675-y

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  • DOI: https://doi.org/10.1007/s10157-018-1675-y

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