Transcriptional Control of the TNF Gene

Abstract

The cytokine TNF is a critical mediator of immune and inflammatory responses. The TNF gene is an immediate early gene, rapidly transcribed in a variety of cell types following exposure to a broad range of pathogens and signals of inflammation and stress. Regulation of TNF gene expression at the transcriptional level is cell type- and stimulus-specific, involving the recruitment of distinct sets of transcription factors to a compact and modular promoter region. In this review, we describe our current understanding of the mechanisms through which TNF transcription is specifically activated by a variety of extracellular stimuli in multiple cell types, including T cells, B cells, macrophages, mast cells, dendritic cells, and fibroblasts. We discuss the role of nuclear factor of activated T cells and other transcription factors and coactivators in enhanceosome formation, as well as the contradictory evidence for a role for nuclear factor κB as a classical activator of the TNF gene. We describe the impact of evolutionarily conserved cis-regulatory DNA motifs in the TNF locus upon TNF gene transcription, in contrast to the neutral effect of single nucleotide polymorphisms. We also assess the regulatory role of chromatin organization, epigenetic modifications, and long-range chromosomal interactions at the TNF locus.

Tumor Necrosis Factor-α 238 G/A Polymorphism and Risk of Hepatocellular Carcinoma: Evidence from a Meta-analysis

“…Because A allele of TNF-α at −238 in the promoter region was found to down-regulate gene expression, TNF-α 238 G/A polymorphism is believed to be involved in the in the carcinogenesis (Falvo et al, 2010;Qidwai et al, 2011). In the past decade, many studies have focused on the relationship between this variant and cancers.…”

Major apoptotic mechanisms and genes involved in apoptosis

“…The resulting TNF functions by binding to two different receptors, TNRF1 and TNFR2, which are also trimeric trans-membrane proteins [90]. TNF is produced by immune cells including activated natural killer cells, T cells, and activated monocytes/macrophages and a wide range of non-immune cells such as fibroblasts [118]. TNF/TNFR signaling is well known to be involved in various cellular functions such as apoptosis, cell proliferation, and differentiation [119].…”

Negative Feed-forward Control of Tumor Necrosis Factor (TNF) by Tristetraprolin (ZFP36) Is Limited by the Mitogen-activated Protein Kinase Phosphatase, Dual-specificity Phosphatase 1 (DUSP1)

“…Indeed, TNF expression is tightly regulated at a molecular level by transcriptional and post-transcriptional mechanisms (2). Whereas transcriptional control involves recruitment of factors, such as nuclear factor (NF)-B, to the TNF promoter, post-transcriptional regulation is conferred via multiple copies of the adenylate-uridylate-rich element (ARE) 2 (3), AUUUA, located in the 3Ј-UTR of the TNF mRNA (4). Such regions are critical for regulating message stability and are targeted by several RNA-binding proteins, including tristetraprolin (also known as zinc finger protein 36 (ZFP36)), human antigen R (HuR or ELAVL1), adenine-uridine-rich element RNA-binding factor-1 (AUF1 or HNRNPD), and K-homology domain splicing regulatory protein (KHSRP) (5)(6)(7)(8)(9).…”

“…Indeed, ZFP36 is modestly up-regulated by glucocorticoids in the human airway epithelial cells as well as in pulmonary A549 and bronchial BEAS-2B epithelial cells and in the airways following glucocorticoid inhalation (16,31,32). 3 Furthermore, a role for ZFP36 in the repression of inflammatory gene expression is indicated (31,33). Given interest in therapeutically targeting MAPK pathways in inflammatory disease and the fact that glucocorticoids induce DUSP1 to reduce MAPK activity, we have used TNF as a model ZFP36 target gene to explore the relationship(s) between the regulation of MAPK activation by DUSP1 with the expression of ZFP36 and effects on downstream gene expression.…”