Accumulation of glutathione disulfide mediates NF-kappaB activation during immune stimulation with CpG DNA.

Article Details

Citation

Copy to clipboard

Kirsch JD, Yi AK, Spitz DR, Krieg AM

Accumulation of glutathione disulfide mediates NF-kappaB activation during immune stimulation with CpG DNA.

Antisense Nucleic Acid Drug Dev. 2002 Oct;12(5):327-40.

PubMed ID

12477282 [ View in PubMed

]

Abstract

Innate immune cells recognize pathogens by detecting molecular patterns that are distinct from those of the host. One such pattern is unmethylated CpG dinucleotides, which are common in bacterial DNA but not in vertebrate genomes. Macrophages respond to such CpG motifs in bacterial DNA or synthetic oligodeoxynucleotides (ODN) by inducing NF-kappaB and secreting proinflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), but the mechanisms regulating this have been unclear. CpG ODN-stimulated cells produce reactive oxygen species (ROS) and have a decreased ratio of intracellular glutathione/glutathione disulfide (GSH/GSSG), indicating a shift to a more oxidized intracellular redox state. To determine whether this may play a role in mediating the CpG-induced macrophage activation, the GSH/GSSG redox state was manipulated in the murine macrophagelike cell line RAW264.7. Treatment of cells with BCNU to inhibit glutathione reductase (GR) enhanced the CpG-induced intracellular oxidation and decreased the GSH/GSSG, with increased activation of NF-kappaB and a doubling in the CpG-induced production of IL-6 and TNF-alpha. Experimental manipulation of the intracellular GSSG concentration during inhibition of cellular prooxidant production demonstrated that increased intracellular GSSG is a primary signal that is directly or indirectly required for CpG-induced NF-kappaB activation but is not in itself sufficient to trigger this in the absence of CpG ODN. These data suggest the existence of a second CpG-induced intracellular signal, independent of GSSG, mediating the activation of innate immunity by bacterial DNA.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Carmustine	Glutathione reductase, mitochondrial	Protein	Humans	Yes	Inhibitor	Details