TNF Pathophysiology

Molecular and Cellular Mechanisms

G. Kollias, P. P. Sfikakis, A. N. Theofilopoulos

• Publisher: S. Karger
• Year: 2010
• Print ISBN: 9783805593830
• eBook ISBN: 9783805593847
• Topic: Medicine
• Subtopic: Genetics in Medicine

TNF is a multifunctional proinflammatory cytokine central to the development and homeostasis of the immune system and a regulator of cell activation, differentiation and death. Recent decades have seen an enormous scientific and clinical interest in the function of TNF in physiology and disease. A vast amount of data has been accumulated at the biochemical, molecular and cellular level, establishing TNF as a prototype for in-depth understanding of the physiological and pathogenic functions of cytokines. This volume covers several current aspects of TNF regulation and function, including transcriptional and posttranscriptional control mechanisms, cellular modes of action, signaling networks that mediate its effect, involvement in pathogenesis and clinical outcomes of TNF antagonists. It combines basic science at the molecular and cellular level with research in animal models of disease and clinical findings to provide a comprehensive review of recent developments in TNF biology. A thorough understanding of the mechanisms by which this key molecular player is produced and functions to regulate cell biology, immunity and disease postulates novel paradigms on how genes contribute to the development and physiology of biological systems. This book is mandatory reading for molecular and cell biologists, immunologists and clinicians interested in TNF function.

Kollias G, Sfikakis PP (eds): TNF Pathophysiology. Molecular and Cellular Mechanisms.
Curr Dir Autoimmun. Basel, Karger, 2010, vol 11, pp 27–60

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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 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.

Copyright © 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 (FcεRI)	IgE + antigen	[10]
NK cell receptor (FcγRIIIA/CD16a)	Anti-CD16, immune complexes	[228]
Other stimuli
Cytokines	Interleukin-1	[221]
	Interleukin-2	[229]
	IFN-γ*	[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]

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, Crohn’s 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...

Table of contents

• Cover Page
• Front Matter
• Cellular Mechanisms of TNF Function in Models of Inflammation and Autoimmunity
• Transcriptional Control of the TNF Gene
• Posttranscriptional Regulation of TNF mRNA: A Paradigm of Signal-Dependent mRNA Utilization and Its Relevance to Pathology
• Role of TNF in Pathologies Induced by Nuclear Factor κB Deficiency
• Type I Interferon: A New Player in TNF Signaling
• T Cells as Sources and Targets of TNF: Implications for Immunity and Autoimmunity
• TNF-α: An Activator of CD4+FoxP3+TNFR2+ Regulatory T Cells
• TNF and Bone
• TNF-α and Obesity
• TNF in Host Resistance to Tuberculosis Infection
• The First Decade of Biologic TNF Antagonists in Clinical Practice: Lessons Learned, Unresolved Issues and Future Directions
• Author Index
• Subject Index