title: The critical role of lipopolysaccharide in the upregulation of aquaporin 4 in glial cells treated with Shiga toxin.
abstract: BACKGROUND
  In 2011, there was an outbreak of Shiga toxin-producing Escherichia coli (STEC) infections in Japan. Approximately 62 % of patients with hemolytic-uremic syndrome also showed symptoms of encephalopathy. To determine the mechanisms of onset for encephalopathy during STEC infections, we conducted an in vitro study with glial cell lines and primary glial cells.
  
  
  RESULTS
  Shiga toxin 2 (Stx-2) in combination with lipopolysaccharide (LPS), or LPS alone activates nuclear factor-κB (NF-κB) signaling in glial cells. Similarly, Stx-2 in combination with LPS, or LPS alone increases expression levels of aquaporin 4 (AQP4) in glial cells. It is possible that overexpression of AQP4 results in a rapid and increased influx of osmotic water across the plasma membrane into cells, thereby inducing cell swelling and cerebral edema.
  
  
  CONCLUSIONS
  We have showed that a combination of Stx-2 and LPS induced apoptosis of glial cells recently. Glial cells are indispensable for cerebral homeostasis; therefore, their dysfunction and death impairs cerebral homeostasis and results in encephalopathy. We postulate that the onset of encephalopathy in STEC infections occurs when Stx-2 attacks vascular endothelial cells of the blood-brain barrier, inducing their death. Stx-2 and LPS then attack the exposed glial cells that are no longer in contact with the endothelial cells. AQP4 is overexpressed in glial cells, resulting in their swelling and adversely affecting cerebral homeostasis. Once cerebral homeostasis is affected in such a way, encephalopathy is the likely result in STEC patients.
authors.affiliation: Department of Physiology, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8640, Japan. ns@med.kanazawa-u.ac.jp.|Department of Pediatrics, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan. ns@med.kanazawa-u.ac.jp.
authors.forename: Naotoshi
authors.initials: N
authors.lastname: Sugimoto
authors.affiliation: Department of Pediatrics, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan. nevergiveup.hue@gmail.com.|Dan Phuong General Hospital, Hanoi, Vietnam. nevergiveup.hue@gmail.com.
authors.forename: Hue
authors.initials: H
authors.lastname: Leu
authors.affiliation: Department of Pediatrics, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan. na230325@yahoo.co.jp.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Inoue
authors.affiliation: Department of Pediatrics, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan. shimizum@staff.kanazawa-u.ac.jp.
authors.forename: Masaki
authors.initials: M
authors.lastname: Shimizu
authors.affiliation: Department of Pediatrics, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan. tomoko-t@staff.kanazawa-u.ac.jp.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Toma
authors.affiliation: Department of Pediatrics, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan. monkuro@staff.kanazawa-u.ac.jp.
authors.forename: Mondo
authors.initials: M
authors.lastname: Kuroda
authors.affiliation: Department of Pediatrics, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan. t9saito@staff.kanazawa-u.ac.jp.
authors.forename: Takekatsu
authors.initials: T
authors.lastname: Saito
authors.affiliation: Department of Pediatrics, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan. taizo@staff.kanazawa-u.ac.jp.
authors.forename: Taizo
authors.initials: T
authors.lastname: Wada
authors.affiliation: Department of Pediatrics, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan. yachie@staff.kanazawa-u.ac.jp.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yachie
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000096:biosynthesis*; D002460:Cell Line; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009457:Neuroglia / Q000378:metabolism*; D051381:Rats; D022621:Shiga Toxin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: C496032:Aqp4 protein, rat; D051401:Aquaporin 4; D008070:Lipopolysaccharides; D022621:Shiga Toxin