Diminished Macrophage Apoptosis and Reactive Oxygen Species Generation after Phorbol Ester Stimulation in Crohn's Disease

• Published in: PloS one Vol. 4; no. 11; p. e7787
• Main Authors: Palmer, Christine D., Rahman, Farooq Z., Sewell, Gavin W., Ahmed, Afshan, Ashcroft, Margaret, Bloom, Stuart L., Segal, Anthony W., Smith, Andrew M.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12.11.2009; Public Library of Science (PLoS)
• Subjects: Acetic acid; Activation; Apoptosis; Arthritis; Bacteria; Cell activation; Cell Biology/Cellular Death and Stress Responses; Cell Survival; Crohn Disease - metabolism; Crohn's Disease; Crohns disease; Cytochrome; Cytochrome c; Defects; Dendritic cells; Deoxyribonucleic acid; Depolarization; Diacylglycerol; Diglycerides; Diglycerides - chemistry; DNA; DNA fragmentation; Drug dosages; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Gastroenterology; Gastroenterology and Hepatology/Inflammatory Bowel Disease; Gastrointestinal system; Gastrointestinal tract; Gastrointestinal Tract - metabolism; Gastrointestinal Tract - microbiology; Homology; Humans; Immunology/Innate Immunity; Inflammation; Inflammatory bowel diseases; Interleukin 6; Interleukin-6 - metabolism; Kinases; Lymphocytes; Macrophages; Macrophages - metabolism; Medicine; Membrane potential; Membrane Potentials; Mitochondria; Mitochondrial DNA; Neutrophils; Oxygen; p53 Protein; Pathogenesis; Phorbol esters; Phorbol Esters - metabolism; Probiotics; Reactive Oxygen Species; Studies; Tetradecanoylphorbol Acetate - pharmacology; Tumor necrosis factor-TNF; Tumor proteins; Tumor Suppressor Protein p53 - metabolism; United Kingdom > UK
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0007787

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. 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. 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.