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Tumor necrosis factor alpha and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of
Abstract:
Binding of peptide hormones to surface membrane receptors leads to the transcription of specific genes within relevant target cells. How these signals are transduced to alter gene expression is largely unknown, but this mechanism probably involves a sequence of enzymatic steps that activate factors in the nucleus that modulate transcription. We now demonstrate that two different peptide hormones, or cytokines, stimulate the human immunodeficiency virus enhancer, and this effect is mediated by nuclear factor (NF) kappa B (nuclear factor that binds the kappa immunoglobulin light chain gene enhancer). These cytokines, tumor necrosis factor alpha and interleukin 1, act on multiple cell types and represent the only naturally occurring activators of this transcription factor among eight cytokines examined. Although NF-kappa B binding can be stimulated by phorbol 12-myristate 13-acetate, tumor necrosis factor alpha acts through an independent mechanism, inducing NF-kappa B binding in HT-2 cells, which did not show increased binding in response to phorbol 12-myristate 13-acetate, and causing superinduction in Jurkat T-lymphoma cells. Tumor necrosis factor alpha is also a more selective activator of T cells than phorbol 12-myristate 13-acetate, having no effect on lymphokine production in EL-4 cells at the same time it induces NF-kappa B. These findings suggest that human immunodeficiency virus gene expression can be induced in T cells without activating lymphokine secretion and that the role of these cytokines in the activation of latent human immunodeficiency virus infection deserves further clinical evaluation. Finally, this link between binding at the surface membrane and stimulation of a specific transcription factor should help define intermediates for these cytokine activation pathways.
Insights
Two cytokines, tumor necrosis factor alpha and interleukin 1, activate nuclear factor kappa B (NF-κB), a key factor in human immunodeficiency virus (HIV) gene expression. This discovery offers new insights into HIV activation pathways.
Area of Science:
- Molecular Biology
- Immunology
- Virology
Background:
- Peptide hormones binding to cell surface receptors initiate gene transcription, but signal transduction pathways remain unclear.
- Understanding how extracellular signals alter gene expression is crucial for cell biology and disease mechanisms.
Purpose of the Study:
- To investigate the mechanism by which peptide hormones and cytokines influence gene transcription.
- To identify specific transcription factors involved in cytokine-mediated gene regulation, particularly concerning human immunodeficiency virus (HIV).
Main Methods:
- Examined the effect of various cytokines on the human immunodeficiency virus enhancer.
- Utilized nuclear factor kappa B (NF-κB) as a key transcription factor for analysis.
- Compared the activity of tumor necrosis factor alpha (TNF-α) and interleukin 1 (IL-1) with phorbol 12-myristate 13-acetate (PMA) in different cell lines (HT-2 and Jurkat T-lymphoma).
Main Results:
- Demonstrated that TNF-α and IL-1 stimulate the HIV enhancer via NF-κB.
- Identified TNF-α and IL-1 as the only naturally occurring activators of NF-κB among eight cytokines tested.
- Showcased TNF-α's independent mechanism of NF-κB induction, distinct from PMA, and its selective activation of T cells without inducing lymphokine secretion.
Conclusions:
- Cytokines TNF-α and IL-1 activate NF-κB, linking cell surface receptor binding to specific transcription factor modulation.
- This cytokine-mediated NF-κB activation can induce HIV gene expression in T cells independently of lymphokine secretion.
- Findings suggest a need for clinical evaluation of cytokine roles in latent HIV activation and provide a framework for understanding cytokine signaling pathways.