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Discrete generation of superoxide and hydrogen peroxide by T cell receptor stimulation: selective regulation of mitogen-activated protein kinase activation and fas ligand expression.

Devadas S, Zaritskaya L, Rhee SG, Oberley L, Williams MS - J. Exp. Med. (2002)

Bottom Line: 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.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).

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Holland Laboratory, American Red Cross, Rockville, MD 20855, USA.

ABSTRACT
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).

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Proposed scheme for TCR-stimulated ROS generation. TCR signaling induces both hydrogen peroxide (H2O2) and superoxide (O2− in a calcium dependent manner in pathway(s) independent of NFAT activation. Hydrogen peroxide production, from an unknown source, regulates ERK activation. Superoxide anion may be derived from an NADH/NADPH oxidase and is required for FasL promoter activation.
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fig8: Proposed scheme for TCR-stimulated ROS generation. TCR signaling induces both hydrogen peroxide (H2O2) and superoxide (O2− in a calcium dependent manner in pathway(s) independent of NFAT activation. Hydrogen peroxide production, from an unknown source, regulates ERK activation. Superoxide anion may be derived from an NADH/NADPH oxidase and is required for FasL promoter activation.

Mentions: Thus, in this study, stimulation via the TCR was shown to induce generation of ROS that served to regulate signal transduction in T lymphocytes. The results suggest that TCR utilizes distinct biochemical pathways to yield production of two discrete species of oxidants, superoxide anion and hydrogen peroxide (Fig. 8) . These ROS, in turn, selectively regulate independent signaling pathways that can affect cell death decisions (FasL) or proliferative responses (ERK). Interestingly, it has recently been suggested that exposure to mild oxidative stress can enhance TCR-stimulated activation of MAP kinases and IL-2 transcription (55), and that synovial fluid T cells isolated from arthritic joints display redox-dependent alterations in signaling pathways (56). This suggests that there are redox sensitive pathways in T cells that may be altered by exposure to exogenous oxidative stress, as may be encountered in disease states such as AIDS or arthritis. The results of this study may suggest that T cells generate their own endogenous oxidative stress to regulate similar pathways.


Discrete generation of superoxide and hydrogen peroxide by T cell receptor stimulation: selective regulation of mitogen-activated protein kinase activation and fas ligand expression.

Devadas S, Zaritskaya L, Rhee SG, Oberley L, Williams MS - J. Exp. Med. (2002)

Proposed scheme for TCR-stimulated ROS generation. TCR signaling induces both hydrogen peroxide (H2O2) and superoxide (O2− in a calcium dependent manner in pathway(s) independent of NFAT activation. Hydrogen peroxide production, from an unknown source, regulates ERK activation. Superoxide anion may be derived from an NADH/NADPH oxidase and is required for FasL promoter activation.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2196010&req=5

fig8: Proposed scheme for TCR-stimulated ROS generation. TCR signaling induces both hydrogen peroxide (H2O2) and superoxide (O2− in a calcium dependent manner in pathway(s) independent of NFAT activation. Hydrogen peroxide production, from an unknown source, regulates ERK activation. Superoxide anion may be derived from an NADH/NADPH oxidase and is required for FasL promoter activation.
Mentions: Thus, in this study, stimulation via the TCR was shown to induce generation of ROS that served to regulate signal transduction in T lymphocytes. The results suggest that TCR utilizes distinct biochemical pathways to yield production of two discrete species of oxidants, superoxide anion and hydrogen peroxide (Fig. 8) . These ROS, in turn, selectively regulate independent signaling pathways that can affect cell death decisions (FasL) or proliferative responses (ERK). Interestingly, it has recently been suggested that exposure to mild oxidative stress can enhance TCR-stimulated activation of MAP kinases and IL-2 transcription (55), and that synovial fluid T cells isolated from arthritic joints display redox-dependent alterations in signaling pathways (56). This suggests that there are redox sensitive pathways in T cells that may be altered by exposure to exogenous oxidative stress, as may be encountered in disease states such as AIDS or arthritis. The results of this study may suggest that T cells generate their own endogenous oxidative stress to regulate similar pathways.

Bottom Line: 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.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).

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Holland Laboratory, American Red Cross, Rockville, MD 20855, USA.

ABSTRACT
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).

Show MeSH