Redox regulation of signal transduction: tyrosine phosphorylation and calcium influx.
Studies presented here show that altering the intracellular redox balance by decreasing glutathione levels profoundly affects early signal transduction events in human T cells. In a T-cell receptor (TCR) signaling model, short-term pretreatment with buthionine sulfoximine, which specifically decreases intracellular glutathione, essentially abrogates the stimulation of calcium influx by anti-CD3 antibodies without significantly impairing other aspects of TCR-initiated signal transduction, such as overall levels of TCR-stimulated tyrosine phosphorylation. In an inflammatory-cytokine signaling model, the failure of tumor necrosis factor alpha to stimulate more than minimal tyrosine phosphorylation in lymphocytes is overcome by buthionine sulfoximine pretreatment--i.e., tumor necrosis factor alpha stimulates extensive tyrosine phosphorylation in glutathione-depleted lymphocytes. These redox-dependent changes in T-cell responsiveness suggest that the glutathione deficiency that we and others have demonstrated in human immunodeficiency virus-infected individuals may contribute significantly to the immunodeficiency and the increased inflammatory reactions in these individuals.
Staal
F J
FJ
Department of Genetics, Stanford University School of Medicine, CA 94305.
Anderson
M T
MT
Staal
G E
GE
Herzenberg
L A
LA
Gitler
C
C
Herzenberg
L A
LA
D017607:Aluminum Compounds / Q000494:pharmacology; D017252:CD3 Complex / Q000502:physiology; D002118:Calcium / Q000502:physiology*; D002460:Cell Line; D016207:Cytokines / Q000494:pharmacology*; D005459:Fluorides / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D010084:Oxidation-Reduction; D010768:Phosphoserine / Q000378:metabolism; D010769:Phosphothreonine / Q000378:metabolism; D019000:Phosphotyrosine; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology*; D013729:Terpenes / Q000494:pharmacology; D019284:Thapsigargin; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D017607:Aluminum Compounds; D017252:CD3 Complex; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; D013729:Terpenes; D010769:Phosphothreonine; D010768:Phosphoserine; D019000:Phosphotyrosine; D014443:Tyrosine; D019284:Thapsigargin; D005978:Glutathione; D005459:Fluorides; D002118:Calcium; C032311:aluminum fluoride