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Pre-Exposure to Oxidative Stress Decreases the Nuclear Factor-B-Dependent Transcription in T Lymphocytes¹

Department of Microbiology and Immunology, University of Tampere Medical School, Tampere, Finland

Reactive oxygen species (ROS) are used as signaling molecules in T cell activation. One of the main targets of ROS is the transcription factor nuclear factor-B (NF-B). NF-B-dependent transcription is inhibited by antioxidants, and the activation is induced or potentiated by ROS. However, chronic oxidative stress is known to reduce the activation of T cells and NF-B. To analyze these phenomena in more detail, we have exposed Jurkat T cells in vitro to oxidative stress (H₂O₂) at various times before or simultaneously with signals known to activate NF-B (phorbol dibutyrate (PDBu) and TNF). Simultaneously applied H₂O₂ strongly potentiated the PDBu- or TNF-induced transcriptional activity of NF-B. In contrast to this, H₂O₂ given 3 to 20 h before the activating signal reduced NF-B-dependent transcriptional activity. This was not due to the oxidation-induced modification of NF-B; cytoplasmic NF-B was able to bind to DNA after dissociation from IB by detergent treatment. H₂O₂ pre-exposure effectively inhibited the PDBu- or TNF-induced phosphorylation and degradation of IB, but H₂O₂ given simultaneously with PDBu or TNF enhanced the degradation. Oxidative stress was also followed by a strongly decreased ability to form intracellular ROS. Taken together, these data indicate that IB phosphorylation is the target of action of ROS, and as the ROS-forming capacity is weaker after chronic oxidative stress, IB is not effectively phosphorylated and degraded, thus leading to decreased NF-B-dependent transcription.