Advisor(s)
Etty Benveniste
Committee Member(s)
Xinbin Chen
Stuart Frank
Louis Nabors
Scott Wilson
Document Type
Dissertation
Date of Award
2008
Abstract
Interleukin-8 (IL-8) is a potent chemoattractant of numerous cells, particularly neutrophils, in the innate immune response. In addition to immune functions, IL-8 is known to contribute to the pathogenesis of a number of diseases, including cancer. Interferon-β (IFN-β), a Type I interferon, inhibits the expression of IL-8, but the details of this effect are not known. In this study we investigate transcriptional control of the IL- 8 gene and the mechanism by which IFN-β exerts inhibitory effects on IL-8. Herein we show that stimulation of U87-MG glioma cells with phorbol 12-myristate 13-acetate (PMA) results in a rapid recruitment of NF-κB p65 to the IL-8 promoter. Additionally, we show that the IL-8 promoter is constitutively acetylated on histones 3 and 4, indicating that the gene is accessible to transcription factors. Positive regulators of gene transcription such as the histone acetyltransferase (HAT) p300 are rapidly recruited to the IL-8 promoter along with RNA polymerase II. At the same time, negative regulators such as the histone deacetylases (HDACs) 1 and 3 that are constitutively present at the IL-8 promoter are dismissed. Upon treatment with IFN-β, however, there are rapid decreases in acetylation of histones 3 and 4 along with decreased levels of NF-κB p65 and RNA polymerase II present at the IL-8 promoter. We show that these promoter effects result in decreased IL-8 promoter activity, mRNA levels and protein levels when cells are treated with IFN-β. iv We also demonstrate that all three components of the Interferon Stimulated Gene Factor 3 (ISGF3) complex, namely the Signal Transducer and Activator of Transcription (STAT) proteins 1 and 2 and the accessory factor Interferon Regulatory Factor-9 (IRF-9), are required for IFN-β to mediate inhibitory effects on IL-8. In contrast to gene induction by this complex, however, STAT-1 and -2 transactivation domains were not required for inhibition by IFN-β. This work defines the promoter-specific events necessary for induction of IL-8 expression in malignant asctrocytoma cells, and the mechanistic requirements for inhibition of IL-8 by IFN-β in these cells.
ProQuest Publication Number
ISBN
978-0-549-57999-1
Recommended Citation
Laver, Travis, "Mechanism Of Interferon-Beta-Mediated Inhibition Of Il-8 Gene Expression" (2008). All ETDs from UAB. 3741.
https://digitalcommons.library.uab.edu/etd-collection/3741
