Discrete generation of superoxide and hydrogen peroxide by T cell receptor stimulation: selective regulation of mitogen-activated protein kinase activation and fas ligand expression.
Receptor-stimulated generation of reactive oxygen species (ROS) has been shown to regulate signal transduction, and previous studies have suggested that T cell receptor (TCR) signals may involve or be sensitive to ROS. In this study, we have shown for the first time that TCR cross-linking induced rapid (within 15 min) generation of both hydrogen peroxide and superoxide anion, as defined with oxidation-sensitive dyes, selective pharmacologic antioxidants, and overexpression of specific antioxidant enzymes. Furthermore, the data suggest the novel observation that superoxide anion and hydrogen peroxide are produced separately by distinct TCR-stimulated pathways. Unexpectedly, TCR-stimulated activation of the Fas ligand (FasL) promoter and subsequent cell death was dependent upon superoxide anion, but independent of hydrogen peroxide, while nuclear factor of activated T cells (NFAT) activation or interleukin 2 transcription was independent of all ROS. Anti-CD3 induced phosphorylation of extracellular signal-regulated kinase (ERK)1/2 required hydrogen peroxide generation but was unaffected by superoxide anion. Thus, antigen receptor signaling induces generation of discrete species of oxidants that selectively regulate two distinct redox sensitive pathways, a proapoptotic (FasL) and a proliferative pathway (ERK).
Devadas
Satish
S
Department of Immunology, Holland Laboratory, American Red Cross, Rockville, MD 20855, USA.
Zaritskaya
Luba
L
Rhee
Sue Goo
SG
Oberley
Larry
L
Williams
Mark S
MS
D000818:Animals; D017209:Apoptosis; D017252:CD3 Complex / Q000378:metabolism; D053222:Fas Ligand Protein; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D006825:Hybridomas; D006861:Hydrogen Peroxide / Q000378:metabolism; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018448:Models, Immunological; D010084:Oxidation-Reduction; D010545:Peroxides / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*
D017252:CD3 Complex; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D016166:Free Radical Scavengers; D008562:Membrane Glycoproteins; D010545:Peroxides; D017382:Reactive Oxygen Species; D011948:Receptors, Antigen, T-Cell; D013481:Superoxides; D006861:Hydrogen Peroxide; D020928:Mitogen-Activated Protein Kinases