title: Role of the advanced glycation end products receptor in Crohn's disease inflammation.
abstract: OBJECTIVE
  To investigate the level of mucosal expression and the involvement of the receptor for the advanced glycation end products (RAGE) in delayed apoptosis and tumor necrosis factor (TNF)-α production in Crohn's disease (CD).
  
  
  METHODS
  Surgical and endoscopic specimens from both inflamed and non-inflamed areas of the ileum and/or colon were collected from 20 and 14 adult CD patients, respectively, and used for the assessment of RAGE expression by means of immunohistochemistry and western blotting analysis. Normal tissues from 21 control subjects were used for comparison. The same polyclonal anti-human RAGE antibody (R and D System) was used in all experimental conditions. RAGE staining was quantized by a score including both the amount of positive cells and intensity of immunoreactivity; cellular pattern was also described. The effects of RAGE blocking on apoptotic rate and TNF-α production were investigated on immune cells freshly isolated from CD mucosa and incubated both with and without the muramyl dipeptide used as antigenic stimulus. Statistical analysis was performed via the test for trend, with regression models to account for intra-patient correlations. A 2-sided P < 0.05 was considered significant.
  
  
  RESULTS
  In inflamed areas, RAGE expression in both the epithelial and lamina propria compartments was higher than control tissues (P = 0.001 and 0.021, respectively), and a cluster of positive cells were usually found in proximity of ulcerative lesions. Similar results were obtained in the lamina propria compartment of non-inflamed areas (P = 0.025). The pattern of staining was membranous and granular cytosolic at the epithelial level, while in the lamina propria it was diffuse cytosolic. When evaluating the amount of protein expression by immunoblotting, a significant increase of both surface area and band intensity (P < 0.0001 for both) was observed in CD inflamed areas compared to control tissue, while in non-inflamed areas a significant increase was found only for band intensity (P < 0.005). Moreover, a significantly lower expression in non-inflamed areas in comparison with inflamed areas was found for both surface area and band intensity (P < 0.0006 for both). Finally, RAGE blocking largely affects both the apoptotic rate of mucosal cells (towards an increase in both non-inflamed and inflamed areas of P < 0.001 and < 0.0001, respectively) and TNF-α secretion (towards a decrease in both non-inflamed and inflamed areas of P < 0.05 and < 0.01, respectively), mainly in the presence of antigenic stimulation.
  
  
  CONCLUSIONS
  RAGE is up-regulated in CD, especially in inflamed areas, and it appears to play a role in the mechanisms involved in chronic inflammation.
authors.affiliation: Rachele Ciccocioppo, Venerina Imbesi, Vincenzo Boccaccio, Elena Betti, Giuseppina Cristina Cangemi, Gino Roberto Corazza, Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, 27100 Pavia, Italy.
authors.forename: Rachele
authors.initials: R
authors.lastname: Ciccocioppo
authors.affiliation: Rachele Ciccocioppo, Venerina Imbesi, Vincenzo Boccaccio, Elena Betti, Giuseppina Cristina Cangemi, Gino Roberto Corazza, Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, 27100 Pavia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Vanoli
authors.affiliation: Rachele Ciccocioppo, Venerina Imbesi, Vincenzo Boccaccio, Elena Betti, Giuseppina Cristina Cangemi, Gino Roberto Corazza, Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, 27100 Pavia, Italy.
authors.forename: Catherine
authors.initials: C
authors.lastname: Klersy
authors.affiliation: Rachele Ciccocioppo, Venerina Imbesi, Vincenzo Boccaccio, Elena Betti, Giuseppina Cristina Cangemi, Gino Roberto Corazza, Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, 27100 Pavia, Italy.
authors.forename: Venerina
authors.initials: V
authors.lastname: Imbesi
authors.affiliation: Rachele Ciccocioppo, Venerina Imbesi, Vincenzo Boccaccio, Elena Betti, Giuseppina Cristina Cangemi, Gino Roberto Corazza, Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, 27100 Pavia, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Boccaccio
authors.affiliation: Rachele Ciccocioppo, Venerina Imbesi, Vincenzo Boccaccio, Elena Betti, Giuseppina Cristina Cangemi, Gino Roberto Corazza, Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, 27100 Pavia, Italy.
authors.forename: Rachele
authors.initials: R
authors.lastname: Manca
authors.affiliation: Rachele Ciccocioppo, Venerina Imbesi, Vincenzo Boccaccio, Elena Betti, Giuseppina Cristina Cangemi, Gino Roberto Corazza, Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, 27100 Pavia, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Betti
authors.affiliation: Rachele Ciccocioppo, Venerina Imbesi, Vincenzo Boccaccio, Elena Betti, Giuseppina Cristina Cangemi, Gino Roberto Corazza, Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, 27100 Pavia, Italy.
authors.forename: Giuseppina Cristina
authors.initials: GC
authors.lastname: Cangemi
authors.affiliation: Rachele Ciccocioppo, Venerina Imbesi, Vincenzo Boccaccio, Elena Betti, Giuseppina Cristina Cangemi, Gino Roberto Corazza, Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, 27100 Pavia, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Strada
authors.affiliation: Rachele Ciccocioppo, Venerina Imbesi, Vincenzo Boccaccio, Elena Betti, Giuseppina Cristina Cangemi, Gino Roberto Corazza, Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, 27100 Pavia, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Besio
authors.affiliation: Rachele Ciccocioppo, Venerina Imbesi, Vincenzo Boccaccio, Elena Betti, Giuseppina Cristina Cangemi, Gino Roberto Corazza, Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, 27100 Pavia, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rossi
authors.affiliation: Rachele Ciccocioppo, Venerina Imbesi, Vincenzo Boccaccio, Elena Betti, Giuseppina Cristina Cangemi, Gino Roberto Corazza, Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, 27100 Pavia, Italy.
authors.forename: Colomba
authors.initials: C
authors.lastname: Falcone
authors.affiliation: Rachele Ciccocioppo, Venerina Imbesi, Vincenzo Boccaccio, Elena Betti, Giuseppina Cristina Cangemi, Gino Roberto Corazza, Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, 27100 Pavia, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Ardizzone
authors.affiliation: Rachele Ciccocioppo, Venerina Imbesi, Vincenzo Boccaccio, Elena Betti, Giuseppina Cristina Cangemi, Gino Roberto Corazza, Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, 27100 Pavia, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Fociani
authors.affiliation: Rachele Ciccocioppo, Venerina Imbesi, Vincenzo Boccaccio, Elena Betti, Giuseppina Cristina Cangemi, Gino Roberto Corazza, Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, 27100 Pavia, Italy.
authors.forename: Piergiorgio
authors.initials: P
authors.lastname: Danelli
authors.affiliation: Rachele Ciccocioppo, Venerina Imbesi, Vincenzo Boccaccio, Elena Betti, Giuseppina Cristina Cangemi, Gino Roberto Corazza, Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, 27100 Pavia, Italy.
authors.forename: Gino Roberto
authors.initials: GR
authors.lastname: Corazza
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis; D016022:Case-Control Studies; D002478:Cells, Cultured; D003106:Colon / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D003424:Crohn Disease / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007082:Ileum / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha
keywords: Apoptosis; Chronic inflammation; Crohn’s disease; Immunohistochemistry; Receptor for advanced glycation end products; Tumor necrosis factor-α