Hydrogen peroxide and oxygen radicals are agents commonly produced during inflammatory processes. In this study, we show that micromolar concentrations of H2O2 can induce the expression and replication of HIV-1 in a human T cell line. The effect is mediated by the NF-kappa B transcription factor which is potently and rapidly activated by an H2O2 treatment of cells from its inactive cytoplasmic form. N-acetyl-L-cysteine (NAC), a well characterized antioxidant which counteracts the effects of reactive oxygen intermediates (ROI) in living cells, prevented the activation of NF-kappa B by H2O2. NAC and other thiol compounds also blocked the activation of NF-kappa B by cycloheximide, double-stranded RNA, calcium ionophore, TNF-alpha, active phorbol ester, interleukin-1, lipopolysaccharide and lectin. This suggests that diverse agents thought to activate NF-kappa B by distinct intracellular pathways might all act through a common mechanism involving the synthesis of ROI. ROI appear to serve as messengers mediating directly or indirectly the release of the inhibitory subunit I kappa B from NF-kappa B.

Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1.

Sixteen years have passed since the description of the nuclear factor-кB (NF-кB) as a regulator of к light-chain gene expression in murine B lymphocytes (Sen & Baltimore, 1986a) During that time, over 4,000 publications have appeared, characterizing the family of Rel/NF-кB transcription factors involved in the control of a large number of normal and pathological cellular processes The physiological functions of NF-кB proteins include immunological and inflammatory responses, developmental processes, cellular growth and modulating effects on apoptosis In addition, these factors are activated in a number of diseases, including cancer, arthritis, acute and chronic inflammatory states, asthma, as well as neurodegenerative and heart diseases

Activators and target genes of Rel/NF-kappaB transcription factors.

The inducible transcription activator NF-κB: regulation by distinct protein subunits

Herpesvirus saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor.

Publisher Summary This chapter highlights NF-кB/Rel protein complex. Associations of the binding and regulatory subunits of NF-кB operate at the center of a variety of different signal pathways. NF-кB can process and integrate instructions that come from the extracellular environment and detect intracellular events originating in either the cytoplasm or the nucleus. NF-кB then transmits this information with astonishing rapidity to the transcriptional machinery by directly binding to a range of different DNA sequences in gene control regions. NF-кB comprises members of a family of dimer-forming proteins with homology to the rel oncogene. NF-кB has the striking appearance of being constitutively present only in B cells of the “appropriate” stage for Ig к light chain gene expression. The functional role of NF-кB is demonstrated by mutational analysis of the к intronic enhancer. The property that gives NF-кB a widespread significance in cellular regulation is its role as a mediator of inducible gene transcription. The key features of NF-кB transcriptional control are that it is fast and versatile and is used in many different gene systems. It also has the important ability to carry signals from the cytoplasm into the nucleus and trans -activate specific genes by binding directly to their promoters.

NF-kappa B and Rel: participants in a multiform transcriptional regulatory system.

The expression of cytomegalovirus alpha (immediate early) genes is under control of an enhancer that carries signals for strong constitutive expression as well as response elements for transactivation by viral proteins. We have used synthetic oligonucleotides representing the 16, 18 and 19 bp repeat elements within the enhancer to investigate the role of virus-induced cellular transcription factors in enhancer activation. We show that the transcription factor NF-kappa B, which binds to the 18 bp repeat, plays a central role in enhancer activation in infected human fibroblasts and that activation is mediated by the product of the viral gene ie1. The simian immunodeficiency virus kappa B site can functionally substitute for the 18 bp element in transient transactivation assays and can also compete efficiently for specific binding to the 18 bp repeat element in vitro. Point mutations in the NF-kappa B site within the 18 bp element disrupt ie1-mediated transactivation and binding. We have found that the characteristics of the 18 bp binding factor from human fibroblasts are indistinguishable from NF-kappa B induced by phorbol ester plus mitogen treatment of T lymphocytes, as determined by gel mobility shift assay as well as protection of the binding site from chemical cleavage. Furthermore, T cell stimulation mediates activation of the viral enhancer via kappa B sites, an observation that may be important in the interaction of cytomegalovirus with the naturally infected human host. Thus, NF-kappa B plays a central role as a target for enhancer activation via viral and cellular factors.

https://www.embopress.org/doi/pdf/10.1002/j.1460-2075.1989.tb08610.x

NF-kappa B activation of the cytomegalovirus enhancer is mediated by a viral transactivator and by T cell stimulation.

For the great number of RNA and DNA viruses that persist in the host following primary infection, two common tenets emerge: viral gene expression is generally downregulated or altered during persistent infection, and the host immune response fails to detect and clear virus-infected cells (Oldstone 1989). While evasion of immune surveillance is important in all persistence, viral gene products may play a direct role as regulatory functions in certain persistent viruses. Herpesvirus latency is associated with a dramatic restriction of viral replication and gene expression, suggesting that these viruses encode gene products that downregulate replication functions in certain target tissues (Stevens 1980; Jordan 1983; Roizman and Sears 1987; Baichwal and Sugden 1988). The best candidates for latency-regulatory genes are in the α (immediate early) class (Leib et al. 1989) as well as genes that are expressed during latent infection (Stroop et al. 1984; Croen et al. 1987; Stevens et al. 1987; Rock et al. 1987; Baichwal and Sugden, 1988).

L. C. Sambucetti

Papers

NF-kappa B activation of the cytomegalovirus enhancer is mediated by a viral transactivator and by T cell stimulation.

Molecular genetic analysis of cytomegalovirus gene regulation in growth, persistence and latency.