diminished macrophage apoptosis and reactive oxygen species generation after phorbol ester stimulation in crohns disease减少巨噬细胞凋亡和活性氧生成后佛波醇酯刺激在克罗恩病.pdfVIP

Diminished Macrophage Apoptosis and Reactive Oxygen Species Generation after Phorbol Ester Stimulation in Crohn’s Disease 1 1,2 1 3 3 Christine D. Palmer , Farooq Z. Rahman , Gavin W. Sewell , Afshan Ahmed , Margaret Ashcroft , 2 1 1 Stuart L. Bloom , Anthony W. Segal , Andrew M. Smith * 1 Department of Medicine, Centre for Molecular Medicine, University College London, London, United Kingdom, 2 Department of Gastroenterology, University College London Hospital, London, United Kingdom, 3 Department of Medicine, Centre for Cell Signalling and Molecular Genetics, University College London, London, United Kingdom 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 st