Overexpression of ATP-activated P2X7 receptors in the intestinal mucosa is implicated in the pathogenesis of Crohn's disease.

Abstract:

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.

journal_name

Inflamm Bowel Dis

authors

Neves AR,Castelo-Branco MT,Figliuolo VR,Bernardazzi C,Buongusto F,Yoshimoto A,Nanini HF,Coutinho CM,Carneiro AJ,Coutinho-Silva R,de Souza HS

doi

10.1097/01.MIB.0000441201.10454.06

subject

Has Abstract

pub_date

2014-03-01 00:00:00

pages

444-57

issue

3

eissn

1078-0998

issn

1536-4844

journal_volume

20

pub_type

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