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

  • Shimpei Yamada
  • Masaki ShimizuEmail author
  • Mondo Kuroda
  • Natsumi Inoue
  • Naotoshi Sugimoto
  • Akihiro Yachie
Original article



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.


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.


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.


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.


IL-33 sST2 Enterohemorrhagic Escherichia coli Hemolytic uremic syndrome 



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.


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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interest.


  1. 1.
    Zoja C, Buelli S, Morigi M. Shiga toxin-associated hemolytic uremic syndrome: pathophysiology of endothelial dysfunction. Pediatr Nephrol. 2010;25:2231–40.CrossRefGoogle Scholar
  2. 2.
    Scheiring J, Andreoli SP, Zimmerhackl LB. Treatment and outcome of Shiga toxin-associated hemolytic uremic syndrome (HUS). Pediatr Nephrol. 2008;23:1749–60.CrossRefGoogle Scholar
  3. 3.
    Hahn JS, Havens PL, Higgins JJ, O’Rourke PP, Estroff JA, Strand R. Neurological complications of hemolytic-uremic syndrome. J Child Neurol. 1989;4:108–13.CrossRefGoogle Scholar
  4. 4.
    Siegler RL. Spectrum of extrarenal involvement in postdiarrheal hemolytic-uremic syndrome. J Pediatr. 1994;125:511–8.CrossRefGoogle Scholar
  5. 5.
    Shiraishi M, Ichiyama T, Matsushige T, Iwaki T, Iyoda K, Fukuda K, et al. Soluble tumor necrosis factor receptor 1 and tissue inhibitor of metalloproteinase-1 in hemolytic uremic syndrome with encephalopathy. J Neuroimmunol. 2008;196:147–52.CrossRefGoogle Scholar
  6. 6.
    Shimizu M, Kuroda M, Sakashita N, Konishi M, Kaneda H, Igarashi N, et al. Cytokine profiles of patients with enterohemorrhagic Escherichia coli O111-induced hemolytic-uremic syndrome. Cytokine. 2012;60:694–700.CrossRefGoogle Scholar
  7. 7.
    Shimizu M, Kuroda M, Inoue N, Konishi M, Igarashi N, Taneichi H, et al. Extensive serum biomarker analysis in patients with enterohemorrhagic Escherichia coli O111-induced hemolytic-uremic syndrome. Cytokine. 2014;66:1–6.CrossRefGoogle Scholar
  8. 8.
    Shimizu M, Inoue N, Kuroda M, Mizuta M, Sugimoto N, Kaneda H, et al. Angiopoietin-1 and -2 as markers for disease severity in hemolytic uremic syndrome induced by enterohemorrhagic Escherichia coli. Clin Exp Nephrol. 2017;21:76–82.CrossRefGoogle Scholar
  9. 9.
    Garlanda C, Dinarello CA, Mantovani A. The interleukin-1 family: back to the future. Immunity. 2013;39:1003–18.CrossRefGoogle Scholar
  10. 10.
    Cayrol C, Girard JP. IL-33: an alarmin cytokine with crucial roles in innate immunity, inflammation and allergy. Curr Opin Immunol. 2014;31:31–7.CrossRefGoogle Scholar
  11. 11.
    Bergers G, Reikerstorfer A, Braselmann S, Graninger P, Busslinger M. Alternative promoter usage of the Fos-responsive gene Fit-1 generates mRNA isoforms coding for either secreted or membrane-bound proteins related to the IL-1 receptor. EMBO J. 1994;13:1176–88.CrossRefGoogle Scholar
  12. 12.
    Iwahana H, Yanagisawa K, Ito-Kosaka A, Kuroiwa K, Tago K, Komatsu N, et al. Different promoter usage and multiple transcription initiation sites of the interleukin-1 receptor-related human ST2 gene in UT-7 and TM12 cells. Eur J Biochem. 1999;264:397–406.CrossRefGoogle Scholar
  13. 13.
    Préfontaine D, Lajoie-Kadoch S, Foley S, Audusseau S, Olivenstein R, Halayko AJ, et al. Increased expression of IL-33 in severe asthma: evidence of expression by airway smooth muscle cells. J Immunol. 2009;183:5094–103.CrossRefGoogle Scholar
  14. 14.
    Matsuyama Y, Okazaki H, Tamemoto H, Kimura H, Kamata Y, Nagatani K, et al. Increased levels of interleukin 33 in sera and synovial fluid from patients with active rheumatoid arthritis. J Rheumatol. 2010;37:18–25.CrossRefGoogle Scholar
  15. 15.
    Buder K, Latal B, Nef S, Neuhaus TJ, Laube GF, Spartà G. Neurodevelopmental long-term outcome in children after hemolytic uremic syndrome. Pediatr Nephrol. 2015;30:503–13.CrossRefGoogle Scholar
  16. 16.
    Gianantonio CA, Vitacco M, Mendilaharzu F, Gallo GE, Sojo ET. The hemolytic uremic syndrome. Nephron. 1973;11:174–92.CrossRefGoogle Scholar
  17. 17.
    Yasuoka S, Kawanokuchi J, Parajuli B, Jin S, Doi Y, Noda M, et al. Production and functions of IL-33 in the central nervous system. Brain Res. 2011;1385:8–17.CrossRefGoogle Scholar
  18. 18.
    Wicher G, Wallenquist U, Lei Y, Enoksson M, Li X, Fuchs B, et al. Interleukin-33 promotes recruitment of microglia/macrophages in response to traumatic brain injury. J Neurotrauma. 2017;34:3173–82.CrossRefGoogle Scholar
  19. 19.
    Cao K, Liao X, Lu J, Yao S, Wu F, Zhu X, et al. IL-33/ST2 plays a critical role in endothelial cell activation and microglia-mediated neuroinflammation modulation. J Neuroinflammation. 2018;15:136.CrossRefGoogle Scholar
  20. 20.
    Gadani SP, Walsh JT, Smirnov I, Zheng J, Kipnis J. The glia-derived alarmin IL-33 orchestrates the immune response and promotes recovery following CNS injury. Neuron. 2015;85:703–9.CrossRefGoogle Scholar
  21. 21.
    Oshikawa K, Kuroiwa K, Tago K, Iwahana H, Yanagisawa KEN, Ohno S, et al. Elevated soluble ST2 protein levels in sera of patients with asthma with an acute exacerbation. Am J Respir Crit Care Med. 2001;164:277–81.CrossRefGoogle Scholar

Copyright information

© Japanese Society of Nephrology 2018

Authors and Affiliations

  1. 1.Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health SciencesKanazawa UniversityKanazawaJapan
  2. 2.Department of Physiology, School of Medicine, Institute of Medical, Pharmaceutical and Health SciencesKanazawa UniversityKanazawaJapan

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