title: IL-33 Signaling Protects from Murine Oxazolone Colitis by Supporting Intestinal Epithelial Function.
abstract: BACKGROUND
  IL-33, a member of the IL-1 cytokine family that signals through ST2, is upregulated in ulcerative colitis (UC); however, the role of IL-33 in colitis remains unclear. IL-33 augments type 2 immune responses, which have been implicated in UC pathogenesis. We sought to determine the role of IL-33 signaling in oxazolone (OXA) colitis, a type 2 cytokine-mediated murine model of UC.
  
  
  METHODS
  Colon mucosal IL-33 expression was compared between pediatric and adult UC and non-IBD patients using immunohistochemistry and real-time PCR. OXA colitis was induced in WT, IL-33, and ST2 mice, and histopathology, cytokine levels, and goblet cells were assessed. Transepithelial resistance was measured across IL-33-treated T84 cell monolayers.
  
  
  RESULTS
  Colon mucosal IL-33 was increased in pediatric patients with active UC and in OXA colitis. IL-33 and ST2 OXA mice exhibited increased disease severity compared with WT OXA mice. OXA induced a mixed mucosal cytokine response, but few differences were observed between OXA WT and IL-33 or ST2 mice. Goblet cells were significantly decreased in IL-33 and ST2 OXA compared with WT OXA mice. IL-33 augmented transepithelial resistance in T84 cells, and this effect was blocked by the ERK1/2 inhibitor PD98,059.
  
  
  CONCLUSIONS
  OXA colitis is exacerbated in IL-33 and ST2 mice. Increased mucosal IL-33 in human UC and murine colitis may be a homeostatic response to limit inflammation, potentially through effects on epithelial barrier function. Further investigation of IL-33 protective mechanisms would inform the development of novel therapeutic approaches.
authors: *Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; †Division of Pediatric Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee; ‡Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; §Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; ‖Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; ¶Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee; **Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee; ††Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee; and ‡‡The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors: Amanda
authors: A
authors: Waddell
authors: Jefferson E
authors: JE
authors: Vallance
authors: Preston D
authors: PD
authors: Moore
authors: Amy T
authors: AT
authors: Hummel
authors: David
authors: D
authors: Wu
authors: Shiva K
authors: SK
authors: Shanmukhappa
authors: Lin
authors: L
authors: Fei
authors: M Kay
authors: MK
authors: Washington
authors: Phillip
authors: P
authors: Minar
authors: Lori A
authors: LA
authors: Coburn
authors: Susumu
authors: S
authors: Nakae
authors: Keith T
authors: KT
authors: Wilson
authors: Lee A
authors: LA
authors: Denson
authors: Simon P
authors: SP
authors: Hogan
authors: Michael J
authors: MJ
authors: Rosen
mesh_terms: D000328:Adult; D000818:Animals; D002648:Child; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D003093:Colitis, Ulcerative / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D020397:Goblet Cells / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000473:pathology; D051379:Mice; D010081:Oxazolone; D060888:Real-Time Polymerase Chain Reaction; D018123:Receptors, Interleukin; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D016207:Cytokines; C486189:Il1rl1 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D018123:Receptors, Interleukin; D010081:Oxazolone