TY - JOUR
T1 - Longitudinal exposure of human T lymphocytes to weak oxidative stress suppresses transmembrane and nuclear signal transduction
AU - Flescher, Eliezer
AU - Ledbetter, Jeffrey A.
AU - Schieven, Gary L.
AU - Vela-Roch, Norma
AU - Fossum, Donna
AU - Dang, Howard
AU - Ogawa, Noriyoshi
AU - Talal, Norman
N1 - Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 1994/12/1
Y1 - 1994/12/1
N2 - Products of polyamine oxidase activity, at micromolar levels and during a period of 2 to 3 days, down-regulate IL-2 mRNA levels and activity in human lymphocytes. We studied whether this suppression was associated with signal transduction abnormalities. We found that polyamine oxidase activity suppresses both anti-CD3-induced IL-2 production and protein tyrosine phosphorylation. Polyamine oxidase activity also caused a reduction in intracellular calcium mobilization after mitogenic stimulation. The most distal step of CD3-mediated signal transduction is dependent upon transcription factors that regulate a set of genes, including IL-2. We found that polyamine oxidase-treated cells exhibited very low DNA binding activity of two such factors: NFAT and NF-κB. On the other hand, AP-1 DNA binding activity was enhanced in polyamine oxidase-treated cells, suggesting a possible role for AP-1 in the human lymphocyte stress response. In accordance with the oxidation dependence of this suppressive mechanism, N-acetylcysteine (NAC; an antioxidant) significantly reversed the polyamine oxidase effects on lymphokine production and signal transduction. These results suggest that NAC contributes, under oxidizing conditions, to the preservation of immune function. In summary, our data suggest that chronic low-level oxidative stress, via suppression of mitogen-induced transmembrane signaling (protein- tyrosine phosphorylation and calcium mobilization), causes a decrease in the DNA binding activity of transcription factors that regulate the IL-2 gene. This results in decreased IL-2 production.
AB - Products of polyamine oxidase activity, at micromolar levels and during a period of 2 to 3 days, down-regulate IL-2 mRNA levels and activity in human lymphocytes. We studied whether this suppression was associated with signal transduction abnormalities. We found that polyamine oxidase activity suppresses both anti-CD3-induced IL-2 production and protein tyrosine phosphorylation. Polyamine oxidase activity also caused a reduction in intracellular calcium mobilization after mitogenic stimulation. The most distal step of CD3-mediated signal transduction is dependent upon transcription factors that regulate a set of genes, including IL-2. We found that polyamine oxidase-treated cells exhibited very low DNA binding activity of two such factors: NFAT and NF-κB. On the other hand, AP-1 DNA binding activity was enhanced in polyamine oxidase-treated cells, suggesting a possible role for AP-1 in the human lymphocyte stress response. In accordance with the oxidation dependence of this suppressive mechanism, N-acetylcysteine (NAC; an antioxidant) significantly reversed the polyamine oxidase effects on lymphokine production and signal transduction. These results suggest that NAC contributes, under oxidizing conditions, to the preservation of immune function. In summary, our data suggest that chronic low-level oxidative stress, via suppression of mitogen-induced transmembrane signaling (protein- tyrosine phosphorylation and calcium mobilization), causes a decrease in the DNA binding activity of transcription factors that regulate the IL-2 gene. This results in decreased IL-2 production.
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M3 - Article
C2 - 7963551
AN - SCOPUS:0028150839
VL - 153
SP - 4880
EP - 4889
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 11
ER -