Kollias G, Sfikakis PP (eds): TNF Pathophysiology. Molecular and Cellular Mechanisms.
Curr Dir Autoimmun. Basel, Karger, 2010, vol 11, pp 27â60
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Transcriptional Control of the TNF Gene
James V. Falvo ¡ Alla V. Tsytsykova ¡ Anne E. Goldfeld
Immune Disease Institute and Harvard Medical School, Boston, Mass., USA
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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 ÎşB 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.
Copyright Š 2010 S. Karger AG, Basel
TNF plays a critical role in the innate and adaptive immune response and in the normal function of lymphocytes, monocytes, macrophages, neutrophils, and dendritic cells [1, 2]. Although TNF was initially described as a product of macrophages [3], later studies demonstrated that the TNF gene is in fact expressed in a wide range of cell types, including T cells, B cells, NK cells, mast cells, dendritic cells, and fibroblasts [4-11]. Although the secretion of TNF as a mature protein is regulated at the transcriptional, posttranscriptional, translational, and posttranslational levels, this review will examine our current understanding of the mechanisms that control activation of TNF gene expression at the level of transcription, the first step in TNF production.
At the level of transcription, the TNF gene is activated in response to a diversity of specific stimuli that are characteristic of cellular activation, inflammation, infection, and stress. Among these stimuli are calcium signaling, such as calcium influx triggered by ionophores; pathogens, such as bacteria and viruses; mitogens, such as phorbol esters; chemical stress, such as osmotic stress, and radiation, such as UV light (table 1). Inducers of TNF gene transcription also include ligands for several classes of receptors, including antigen receptors, such as the T cell receptor; pattern recognition receptors, such as Toll-like receptors [12], and receptors for cytokines, including the two cognate receptors for TNF itself (table 1).
Table 1. Inducers of TNF transcription. Certain stimuli (asterisk) require a costimulus in some cell types.
| Stimuli | Reference |
PRR ligands | | |
TLR2 | Peptidoglycan (Gram-positive bacteria) | [214] |
| Atypical LPS (P. gingivalis) | [215] |
TLR2/TLR6 | Lipoteichoic acid (Gram-positive bacteria) | [216] |
| Diacylated lipoproteins, e.g. MALP-2 | [217] |
| Zymosan | [218] |
TLR3 | Double-stranded RNA, e.g. poly (I:C) | [219] |
TLR4 | LPS (Gram-negative bacteria) | [220, 221] |
| Synthetic lipid A | [222] |
| Taxol | [223] |
TLR7 | Loxoribine | [224] |
TLR7/TLR8 | Single-stranded RNA, e.g. poly I, poly C | [225] |
| Imidazoquinoline compounds, e.g. imiquimod | [226] |
TLR9 | Bacterial CpG-DNA | [225] |
NOD2 | Muramyl dipeptide | [227] |
Antigen receptor ligands | | |
T cell receptor | Anti-CD3 | [15] |
| PHA | [4] |
B cell receptor | Anti-IgG | [13] |
Fc receptor ligands | | |
Mast cell receptor (FcÎľRI) | IgE + antigen | [10] |
NK cell receptor (FcÎłRIIIA/CD16a) | Anti-CD16, immune complexes | [228] |
Other stimuli | | |
Cytokines | Interleukin-1 | [221] |
| Interleukin-2 | [229] |
| IFN-Îł* | [230] |
| Granulocyte-macrophage colony stimulating factor (GM-CSF) | [231] |
| TNF | [232] |
Mitogens | Concanavalin A | [233] |
| PMA* | [221] |
Superantigens | Staphylococcal toxic shock syndrome toxin-1 | [234] |
| Staphylococcal enterotoxin B | [234] |
Phosphatase inhibitors | Okadaic acid | [235, 236] |
| Calyculin A | [235] |
Calcium ionophore | Ionomycin* | [15] |
Radiation | UV light | [237] |
| X-rays | [238] |
Osmotic stress | Raffinose | [45] |
High glucose | | [239] |
Silica particles | | [240] |
Bacteria | Listeria monocytogenes | [241, 242] |
| Staphylococcus aureus | [7] |
| Mycobacterium tuberculosis | [243] |
| Salmonella typhimurium | [242] |
| Escherichia coli | [244] |
Viruses | Sendai virus | [245] |
| Human cytomegalovirus | [246] |
| Vesicular stomatitis virus | [219] |
| Herpes simplex virus type II | [219] |
Protozoans | Plasmodium falciparum | [247] |
| Trypanosoma cruzi | [248] |
| Schistosoma mansoni | [249] |
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Notably, induction of TNF gene transcription after exposure to certain stimuli in specific cell types is paradigmatic of an immediate early gene. For example, after T and B cell activation or after lipopolysaccharide (LPS) stimulation of monocytes, TNF mRNA is transcribed within minutes and is independent of de novo protein synthesis [13-15]. In T cells in particular, TNF is one of the first genes expressed after cellular activation and is one of the few genes that can be induced by signaling through the T cell receptor in the absence of protein synthesis [15] and a CD28 costumulatory signal [15, 16]. Furthermore, the calcium influx component of T cell activation alone can induce TNF transcription [15].
Tight control of TNF expression in specific cell types and after specific stimuli is essential for cellular homeostasis and normal physiology in humans, as evidenced by the finding that dysregulated TNF levels are associated with multiple disease states, including asthma, rheumatoid arthritis, cardiovascular diseases, Crohnâs disease, type II diabetes, eczema, multiple sclerosis, psoriasis, systemic lupus erythematosus, septic shock, and several different forms of cancer [17, 18]. Dysregulation of TNF expression has also been linked to differential susceptibility to several major infectious diseases including tuberculosis and cerebral malaria, when too little or too much TNF is produced, respectively [19, 20]. Thus, the study of TNF gene regulation not only provides an outstanding model system for the study of cell type- and stimulus-specific eukaryotic gene regulation, but also has direct translational implications for understanding a variety of human diseases. The understanding of basic regulatory pathways and identification of mediators leading to TNF gene expression in particular cell types and tissues can provide targets for the design and development of clinically important therapeutic agents that modulate its expression.
Cell Type- and Stimulus-Specific Regulation of TNF Gene Transcription
TNF gene transcription is regulated by nucleoprotein complexes known as enhanceosomes [21-24]. Enhanceosomes consist of sets of transcription factors and coactivators that associate in a higher-order structure with enhancer or promoter regions of a gene and then functio...