Palmer, CD; Rahman, FZ; Sewell, GW; Ahmed, A; Ashcroft, M; Bloom, SL; Segal, AW; Palmer, CD; Rahman, FZ; Sewell, GW; Ahmed, A; Ashcroft, M; Bloom, SL; Segal, AW; Smith, AM; - view fewer (2009) Diminished Macrophage Apoptosis and Reactive Oxygen Species Generation after Phorbol Ester Stimulation in Crohn's Disease. PLoS ONE , 4 (11) , Article e7787. 10.1371/journal.pone.0007787.

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Abstract

Background: Crohn's Disease (CD) is a chronic relapsing disorder characterized by granulomatous inflammation of the gastrointestinal tract. Although its pathogenesis is complex, we have recently shown that CD patients have a systemic defect in macrophage function, which results in the defective clearance of bacteria from inflammatory sites.Methodology/Principal Findings: Here we have identified a number of additional macrophage defects in CD following diacylglycerol (DAG) homolog phorbol-12-myristate-13-acetate (PMA) activation. We provide evidence for decreased DNA fragmentation, reduced mitochondrial membrane depolarization, impaired reactive oxygen species production, diminished cytochrome c release and increased IL-6 production compared to healthy subjects after PMA exposure. The observed macrophage defects in CD were stimulus-specific, as normal responses were observed following p53 activation and endoplasmic reticulum stress.Conclusion: These findings add to a growing body of evidence highlighting disordered macrophage function in CD and, given their pivotal role in orchestrating inflammatory responses, defective apoptosis could potentially contribute to the pathogenesis of CD.

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