Diminished macrophage apoptosis and reactive oxygen species generation after phorbol ester stimulation in Crohn's disease.
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.
Palmer
Christine D
CD
Department of Medicine, Centre for Molecular Medicine, University College London, London, UK.
Rahman
Farooq Z
FZ
Sewell
Gavin W
GW
Ahmed
Afshan
A
Ashcroft
Margaret
M
Bloom
Stuart L
SL
Segal
Anthony W
AW
Smith
Andrew M
AM
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
D004075:Diglycerides; D015850:Interleukin-6; D010703:Phorbol Esters; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D013755:Tetradecanoylphorbol Acetate