Abstract
Glucose-6-phosphate dehydrogenase (G6PD) provides the reducing agent NADPH to meet the cellular needs for reductive biosynthesis and the maintenance of redox homeostasis. G6PD-deficient cells experience a high level of oxidative stress and an increased susceptibility to viral infections. Cyclooxygenase-2 (COX-2) is a key mediator in the regulation of viral replication and inflammatory response. In the current study, the role of G6PD on the inflammatory response was determined in both scramble control and G6PD-knockdown (G6PD-kd) A549 cells upon tumor necrosis factor-α (TNF-α) stimulation. A decreased expression pattern of induced COX-2 and reduced production of downstream PGE2 occurred upon TNF-α stimulation in G6PD-kd A549 cells compared with scramble control A549 cells. TNF-α-induced antiviral activity revealed that decreased COX-2 expression enhanced the susceptibility to coronavirus 229E infection in G6PD-kd A549 cells and was a result of the decreased phosphorylation levels of MAPK (p38 and ERK1/2) and NF-κB. The impaired inflammatory response in G6PD-kd A549 cells was found to be mediated through NADPH oxidase (NOX) signaling as elucidated by cell pretreatment with a NOX2-siRNA or NOX inhibitor, diphenyleneiodonium chloride (DPI). In addition, NOX activity with TNF-α treatment in G6PD-kd A549 cells was not up-regulated and was coupled with a decrease in NOX subunit expression at the transcriptional level, implying that TNF-α-mediated NOX signaling requires the participation of G6PD. Together, these data suggest that G6PD deficiency affects the cellular inflammatory response and the decreased TNF-α-mediated antiviral response in G6PD-kd A549 cells is a result of dysregulated NOX/MAPK/NF-κB/COX-2 signaling.
Highlights
Glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose monophosphate shunt, is ubiquitously expressed in human tissues [1]
Inhibition of tumor necrosis factor-α (TNF-α)-induced COX-2 expression by celecoxib (COX-2 inhibitor) enhanced viral replication in scramble control cells but not in G6PD-kd A549 cells. These results indicate that TNF-α-induced COX-2 expression inhibits viral replication; increased susceptibility to viral infection in G6PD-kd A549 cells may occur by an impaired inflammatory response upon cytokine stimulation
The present study is the first to show that G6PD knockdown inhibits MAPKs and NF-κB signaling upon TNF-α treatment, resulting in a significant decrease in COX-2 expression and PGE2 production
Summary
Glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose monophosphate shunt, is ubiquitously expressed in human tissues [1]. G6PD deficiency affects cellular functions in nucleated cells, including dysregulated cellular signaling, increased cell senescence or apoptosis and enhanced susceptibility to viral infection [1]. Knockdown of G6PD by RNA interference renders HepG2 cells highly susceptible to H2O2-induced cell death because of impaired dephosphorylation signaling [7]. G6PD increases the activation of the p38 MAPK (Mitogen-activated protein kinases) and NF-κB (Nuclear factor of kappa light polypeptide gene enhancer in B-cells) pathways, which may lead to an increased inflammatory response [8]. These findings indicate that the G6PD plays an important role in modulating cellular signaling and physiological responses
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