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Overexpression of ATP-activated P2X7 Receptors in the Intestinal Mucosa Is Implicated in the Pathogenesis of Crohnʼs Disease

2014; Oxford University Press; Volume: 20; Issue: 3 Linguagem: Inglês

10.1097/01.mib.0000441201.10454.06

1536-4844

Adriane R. Neves, Morgana T. Castelo-Branco, Vanessa Ribeiro Figliuolo, Cláudio Bernardazzi, Fernanda Buongusto, Agnes N. Yoshimoto, Hayandra F. Nanini, Cláudia Mara Lara Melo Coutinho, Antonio José V. Carneiro, Robson Coutinho‐Silva, Heitor Siffert Pereira de Souza,

Eosinophilic Esophagitis

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. 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. 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. 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.