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.

Macrophage Glucose-6-Phosphate Dehydrogenase Stimulates Proinflammatory Responses with Oxidative Stress

“…For example, macrophages derived from G6PD-deficient mice exhibit more anti-inflammatory potential than those from wild-type (WT) mice (42). Also, mononuclear cells from G6PD-deficient patients secret fewer proinflammatory cytokines than those from normal subjects (43).…”

Regulation of LPS stimulated ROS production in peritoneal macrophages from alloxan-induced diabetic rats: Involvement of high glucose and PPARγ

“…NADPH is an essential cellular coenzyme and its level is sustained by NADP + dependent cytosolic dehydrogenases, named glucose-6-phosphate dehydrogenase (G6PD), isocitrate dehydrogenase (IDH) and malate dehydrogenase (MDH). Impaired NADPH production by reduced G6PD activity is associated with augmented IL-10 production and redox dependent signaling in mouse peritoneal macrophages (Wilmanski et al, 2005).…”

An In vivo Drug Screening Model Using Glucose-6-Phosphate Dehydrogenase Deficient Mice to Predict the Hemolytic Toxicity of 8-Aminoquinolines

“…Animals were phenotyped with respect to G6PD enzyme activity by using tail vein blood tested in a G6PD enzyme activity assay kit from Trinity Biotech (Berkeley Heights, NJ) following the manufacturer's instructions. 13,14 Drugs. Primaquine, pamaquine, and mefloquine were obtained from ASH Stevens Inc. (Detroit, MI).…”

“…In this study, we tested whether a G6PDD mouse model, [11][12][13][14] with a moderated degree of G6PD deficiency (10-15% of normal enzyme activity) is similar to that seen in the most common African type A-G6PDD phenotype in humans, and could be used to predict primaquine-induced hemolysis.…”