title: Augmented IL-10 production and redox-dependent signaling pathways in glucose-6-phosphate dehydrogenase-deficient mouse peritoneal macrophages.
abstract: Glucose-6-phosphate dehydrogenase (G6PD) supports cellular antioxidant pathways. G6PD deficiency is associated with malaria protection but was shown to worsen the clinical course to injury. This study tested whether G6PD deficiency manifests in altered cytokine responses using peritoneal macrophages from a G6PD-deficient mouse model with a degree of defect similar to the common type A(-) human G6PD deficiency. Lipopolysaccharide (LPS)-induced interleukin (IL)-10 and IL-12 production was doubled in G6PD-deficient macrophages compared with wild-type (WT). Protein kinase C (PKC) activation by phorbol-ester prior to LPS resulted in a fivefold greater IL-10 production in G6PD-deficient macrophages compared with WT. Interferon-gamma treatment prior to LPS augmented IL-12 production in G6PD-deficient and WT macrophages and partially inhibited IL-10 production by G6PD-deficient macrophages. The antioxidants (N-acetyl-L-cysteine and glutathione ethyl-ester) blunted IL-10 and IL-12 production, indicating a role for oxidative stress in the observed response differences between deficient and WT macrophages. LPS-induced activation of nuclear factor-kappaB, cyclic adenosine monophosphate response element-binding protein, and specificity protein 3 was augmented in G6PD-deficient cells compared with WT. The PKCdelta inhibitor Rottlerin inhibited IL-10 and IL-12 production at different 50% effective-dose concentrations between deficient and WT macrophages, indicating elevated PKCdelta activity in deficient cells. This study reveals that activated G6PD-deficient macrophages display an augmented production of cytokines with a prominent impact on IL-10 production. The altered cytokine responses are associated with augmented activation of redox-dependent transcription factors and PKCdelta. Alterations in signaling pathways and associated changes in cytokine production may play a role in modulating the inflammatory responses following bacterial or malarial infections in G6PD deficiency.
authors.affiliation: Graduate School of Biomedical Sciences, UMDNJ-New Jersey Medical School, Newark, 07103, USA.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Wilmanski
authors.forename: Muhammad
authors.initials: M
authors.lastname: Siddiqi
authors.forename: Edwin A
authors.initials: EA
authors.lastname: Deitch
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Spolarics
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics*; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D016753:Interleukin-10 / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051745:Protein Kinase C-delta; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma; D005954:Glucosephosphate Dehydrogenase; C497259:Prkcd protein, mouse; D011493:Protein Kinase C; D051745:Protein Kinase C-delta