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Overexpression of ATP-activated P2X7 Receptors in the Intestinal Mucosa Is Implicated in the Pathogenesis of Crohn's Disease

Neves, Adriane R. MD*; Castelo-Branco, Morgana T. L. PhD; Figliuolo, Vanessa R. PhD; Bernardazzi, Claudio MSc*; Buongusto, Fernanda MD*; Yoshimoto, Agnes MD*; Nanini, Hayandra F. BSc*,§; Coutinho, Claudia M. L. M. PhD§,‖; Carneiro, Antonio José V. MD, PhD*; Coutinho-Silva, Robson PhD; de Souza, Heitor S. P. MD, PhD*

doi: 10.1097/01.MIB.0000441201.10454.06
Original Basic Science Articles

Background: Extracellular nucleotides released in conditions of cell stress alert the immune system from tissue injury or inflammation. We hypothesized that the P2X7 receptor (P2X7-R) could regulate key elements in inflammatory bowel disease pathogenesis.

Methods: Colonoscopy samples obtained from patients with Crohn's disease (CD), ulcerative colitis, and controls were used to analyze P2X7-R expression by RT and real-time PCR, immunohistochemistry, and confocal microscopy. Inflammatory response was determined by the levels of cytokines by enzyme-linked immunosorbent assay in cultures of intestinal explants. Apoptosis was determined by the TUNEL assay. P2X7-R−/− C57BL/6 mice were treated with trinitrobenzene sulfonic acid or dextran sulfate sodium (DSS) for inducing colitis.

Results: P2X7-R was expressed in higher levels in inflamed CD epithelium and lamina propria, where it colocalizes more with dendritic cells and macrophages. Basal levels of P2X7-R mRNA were higher in CD inflamed mucosa compared with noninflamed CD and controls and were upregulated after interferon-γ in controls. Apoptotic rates were higher in CD epithelium and lamina propria compared with ulcerative colitis and controls. Levels of tumor necrosis factor-α, interleukin (IL)-1β, and IL-17 were higher, whereas IL-10 was lower in CD compared with controls. Levels of tumor necrosis factor-α-α and interleukin-1β increased after adenosine-triphosphate and decreased after KN62 treatment in CD. P2X7-R−/− animals did not develop trinitrobenzene sulfonic acid or DSS colitis.

Conclusions: The upregulation of P2X7-R in CD inflamed mucosa is consistent with the involvement of purinoceptors in inflammation and apoptosis. These observations may implicate purinergic signaling in the pathogenesis of intestinal inflammation, and the P2X7-R may represent a novel therapeutic target in CD.

Article first published online 9 January 2014

*Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil;

Laboratório de Imunologia Celular, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil;

Programa de Imunobiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil;

§Laboratório de Inovações em Terapias, Ensino e Bioprodutos-LITEB, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil; and

Departamento de Biologia Celular e Molecular, Instituto de Biologia, Universidade Federal Fluminense, Niterói, Brasil.

Reprints: Heitor S. P. de Souza, MD, PhD, Laboratório Multidisciplinar de Pesquisa (sub-solo), Hospital Universitário, Universidade Federal do Rio de Janeiro, Rua Prof. Rodolpho Paulo Rocco 255, Ilha do Fundão, Rio de Janeiro 21941-913, Brazil (e-mail: hsouza@hucff.ufrj.br).

Supported by grants from Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro-FAPERJ and Conselho Nacional de Desenvolvimento Científico e Tecnológico–CNPq.

The authors have no conflicts of interest to disclose.

Received November 23, 2013

Accepted December 4, 2013

© Crohn's & Colitis Foundation of America, Inc.
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