title: Diminished macrophage apoptosis and reactive oxygen species generation after phorbol ester stimulation in Crohn's disease.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, Centre for Molecular Medicine, University College London, London, UK.
authors.forename: Christine D
authors.initials: CD
authors.lastname: Palmer
authors.forename: Farooq Z
authors.initials: FZ
authors.lastname: Rahman
authors.forename: Gavin W
authors.initials: GW
authors.lastname: Sewell
authors.forename: Afshan
authors.initials: A
authors.lastname: Ahmed
authors.forename: Margaret
authors.initials: M
authors.lastname: Ashcroft
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Bloom
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Segal
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Smith
mesh_terms: D017209:Apoptosis; D002470:Cell Survival; D003424:Crohn Disease / Q000378:metabolism*; D004075:Diglycerides / Q000737:chemistry; D004721:Endoplasmic Reticulum / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000378:metabolism / Q000382:microbiology*; D006801:Humans; D007249:Inflammation; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008564:Membrane Potentials; D010703:Phorbol Esters / Q000378:metabolism*; D017382:Reactive Oxygen Species; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D004075:Diglycerides; D015850:Interleukin-6; D010703:Phorbol Esters; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D013755:Tetradecanoylphorbol Acetate