Palmer CD, Rahman FZ, Sewell GW et al. PLoS One 2009;4:e7787.
These authors previously proposed the hypothesis that defective macrophage function underlies the development of Crohn’s disease. In this study, further specific functional macrophage defects including impaired reactive oxygen species production, diminished cytochrome C release, and increased interleukin-6 following phorbol-12-myristate-13-acetate (PMA)-activation were shown in patients with Crohn’s disease in comparison with healthy subjects.
A recently postulated theory for the pathogenesis of Crohn’s disease is a systemic failure of acute inflammation that leads to a diminished pro-inflammatory cytokine release, reduced neutrophil recruitment, and the persistence of bacterial products within the tissue. These, in turn, potentially drive chronic inflammation. Recent studies suggest that this defect is at the macrophage level, which results in the defective clearance of bacteria from inflammatory sites (e.g. [1]). In the present study, Palmer and colleagues identified a number of additional macrophage defects in Crohn’s disease in experiments in which mononuclear cells were stimulated with the diacylglycerol (DAG) homologue phorbol-12-myristate-13-acetate (PMA). PMA exerts its effects via activation of DAG-responsive proteins and thus targets a number of potential pathways in human macrophages. Protein kinase C (PKC) family members are especially sensitive to PMA activation and have been implicated in the induction of both apoptosis as well as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity.