Vitamin C inhibits granulocyte macrophage-colony-stimulating factor-induced signaling pathways.
Vitamin C is present in the cytosol as ascorbic acid, functioning primarily as a cofactor for enzymatic reactions and as an antioxidant to scavenge free radicals. Human granulocyte macrophage-colony-stimulating factor (GM-CSF) induces an increase in reactive oxygen species (ROS) and uses ROS for some signaling functions. We therefore investigated the effect of vitamin C on GM-CSF-mediated responses. Loading U937 cells with vitamin C decreased intracellular levels of ROS and inhibited the production of ROS induced by GM-CSF. Vitamin C suppressed GM-CSF-dependent phosphorylation of the signal transducer and activator of transcription 5 (Stat-5) and mitogen-activated protein (MAP) kinase (Erk1 and Erk2) in a dose-dependent manner as was phosphorylation of MAP kinase induced by both interleukin 3 (IL-3) and GM-CSF in HL-60 cells. In 293T cells transfected with alpha and beta GM-CSF receptor subunits (alphaGMR and betaGMR), GM-CSF-induced phosphorylation of betaGMR and Jak-2 activation was suppressed by vitamin C loading. GM-CSF-mediated transcriptional activation of a luciferase reporter construct containing STAT-binding sites was also inhibited by vitamin C. These results substantiate the importance of ROS in GM-CSF signaling and indicate a role for vitamin C in downmodulating GM-CSF signaling responses. Our findings point to vitamin C as a regulator of cytokine redox-signal transduction in host defense cells and a possible role in controlling inflammatory responses.
Cárcamo
Juan M
JM
Program in Molecular Pharmacology and Therapeutics, Department of Clinical Chemistry and Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Bórquez-Ojeda
Oriana
O
Golde
David W
DW
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004336:Drug Antagonism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006706:Homeostasis; D006801:Humans; D008894:Milk Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D017382:Reactive Oxygen Species; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020928:Mitogen-Activated Protein Kinases; D001205:Ascorbic Acid