title: Endoplasmic reticulum stress, unfolded protein response and altered T cell differentiation in necrotizing enterocolitis.
abstract: BACKGROUND
  Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) play important roles in chronic intestinal inflammation. Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in preterm infants and is characterized by acute intestinal inflammation and necrosis. The objective of the study is to investigate the role of ER stress and the UPR in NEC patients.
  
  
  METHODS
  Ileal tissues from NEC and control patients were obtained during surgical resection and/or at stoma closure. Splicing of XBP1 was detected using PCR, and gene expression was quantified using qPCR and Western blot.
  
  
  RESULTS
  Splicing of XBP1 was only detected in a subset of acute NEC (A-NEC) patients, and not in NEC patients who had undergone reanastomosis (R-NEC). The other ER stress and the UPR pathways, PERK and ATF6, were not activated in NEC patients. A-NEC patients showing XBP1 splicing (A-NEC-XBP1s) had increased mucosal expression of GRP78, CHOP, IL6 and IL8. Similar results were obtained by inducing ER stress and the UPR in vitro. A-NEC-XBP1s patients showed altered T cell differentiation indicated by decreased mucosal expression of RORC, IL17A and FOXP3. A-NEC-XBP1s patients additionally showed more severe morphological damage and a worse surgical outcome. Compared with A-NEC patients, R-NEC patients showed lower mucosal IL6 and IL8 expression and higher mucosal FOXP3 expression.
  
  
  CONCLUSIONS
  XBP1 splicing, ER stress and the UPR in NEC are associated with increased IL6 and IL8 expression levels, altered T cell differentiation and severe epithelial injury.
authors.affiliation: Division of Neonatology, Department of Pediatrics, Erasmus MC-Sophia, Rotterdam, the Netherlands ; Department of Pediatrics, Emma Children's Hospital - AMC, Amsterdam, The Netherlands.
authors.forename: Peng
authors.initials: P
authors.lastname: Lu
authors.forename: Marie-Chantal
authors.initials: MC
authors.lastname: Struijs
authors.forename: Jiaping
authors.initials: J
authors.lastname: Mei
authors.forename: Janneke
authors.initials: J
authors.lastname: Witte-Bouma
authors.forename: Anita M
authors.initials: AM
authors.lastname: Korteland-van Male
authors.forename: Adrianus C J M
authors.initials: AC
authors.lastname: de Bruijn
authors.forename: Johannes B
authors.initials: JB
authors.lastname: van Goudoever
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Renes
mesh_terms: D015153:Blotting, Western; D002454:Cell Differentiation / Q000276:immunology*; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D020345:Enterocolitis, Necrotizing / Q000276:immunology* / Q000503:physiopathology*; D005260:Female; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D007231:Infant, Newborn; D007234:Infant, Premature; D015850:Interleukin-6 / Q000276:immunology; D016209:Interleukin-8 / Q000276:immunology; D008297:Male; D016133:Polymerase Chain Reaction; D000071701:Regulatory Factor X Transcription Factors; D018709:Statistics, Nonparametric; D013601:T-Lymphocytes / Q000276:immunology*; D014157:Transcription Factors / Q000378:metabolism; D056811:Unfolded Protein Response / Q000502:physiology*; D000071717:X-Box Binding Protein 1
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human