Physiological functions of tumor necrosis factor and the consequences of its pathologic overexpression or blockade: Mouse models

https://doi.org/10.1016/j.cytogfr.2008.04.010Get rights and content

Abstract

TNF is an exciting cytokine which has helped to establish many paradigms in immunology. Although TNF itself has found only very limited use in the clinic, anti-cytokine therapy, which targets this single molecule, has enjoyed astounding success in treatment of a growing number of human diseases. However, since TNF mediates unique physiologic functions, in particular those related to host defense, TNF blockade may result in unwanted consequences. Much of our understanding about TNF intrinsic functions in the body, as well as about consequences of its overexpression and ablation, is based on studying phenotypes of various genetically engineered mice. Here we review mouse studies aimed at understanding TNF physiologic functions using transgenic and knockout models, and we discuss additional mouse models that may be helpful in the future.

Introduction

Tumor necrosis factor (TNF, TNFα) was discovered because of its striking anti-tumor activity in mice [1]. Under a different name the same molecule was later purified and cloned by Cerami and co-workers [2]. Today's knowledge puts TNF downstream of many, if not all, pattern-recognition receptors, including Toll-like receptors [3], as well as various cytokine receptors and the T-cell receptor (TCR). Although TNF was initially identified as a product of activated macrophages, and its production was greatly enhanced by challenging mice with the combination of Mycobacteria and bacterial endotoxin [1], it was later found to be produced by many types of leukocytes, as well as by some non-hematopoietic cells (for review see [4]). Since the main signaling receptor, TNFR1 or p55, is expressed on most cell lineages, one can expect that communications between cells via TNF are complex and may have local as well as global consequences.

Pre-knockout studies identified two important opposite functions of TNF in host defense: a seemingly “deleterious” one, due to systemic overproduction which resulted in lethal septic shock [5], and an apparent “beneficial” effect due to the stimulation of protective granuloma formation during mycobacterial infections [6], [7]. Later studies utilizing knockout mice uncovered a constellation of beneficial and detrimental effects that TNF may exert in the body. Even before the whole range of intrinsic biological effects of TNF was revealed through mouse studies [8], [9], [10], [11], [12], [13], [14], pathologic consequences of TNF production were noticed in humans, and, as a result, anti-TNF therapy was proposed [15]. The underlying concept behind this therapeutic approach is based on the widely publicized notion of “bad TNF” [16], neglecting somewhat the many beneficial and unique functions of TNF identified through knockout studies. However, the successful application of anti-TNF treatment for a growing list of autoimmune and other diseases, where patients remain on continuous TNF blockage for the rest of their lives, reinforced interest in TNF biology [17], [18].

In this chapter we review mouse studies aimed at understanding TNF intrinsic physiologic functions – both the seemingly deleterious and the seemingly beneficial – using numerous transgenic and knockout animal models.

Section snippets

Overview of TNF functions revealed in TNF- and TNFR-knockout studies

In the first knockout mice which highlighted critical TNF functions, it was TNF receptor I (TNFR1, p55) rather than the cytokine itself that was ablated by gene targeting [19], [20]. Two main functions of TNFR signaling were reported: its protective role in intracellular bacterial infections (Listeria), and its detrimental role in LPS/D-gal mediated liver toxicity [19], [20]. Since at that time lymphotoxin-alpha (LTα, formerly known as TNF-β), a TNF-like cytokine produced by activated

Conclusions and perspectives

The extraordinary success of anti-TNF therapy in several autoimmune diseases with inflammatory component has also posed many important questions. Considering a number of clearly beneficial and non-redundant TNF functions in vivo, reviewed in this chapter, the main question is how one can systemically and continuously block TNF signaling and yet avoid complications due to the loss of protective and immune functions mediated by TNF.

One possible consideration is that in clinical protocols of TNF

Acknowledgements

We thank Drs. Nancy Rice and Peter Lemansky for critical comments on the manuscript. This work was supported by MCB grants from the Russian Academy of Sciences, SFB633 from DFG (Deutsche Forschungsgemeinschaft) and by FP6 TB REACT grant. S.A.N. is International Research Scholar of the Howard Hughes Medical Institute.

Andrei Kruglov is PhD student at the Faculty of Bioengineering and Bioinformatics, Moscow State University and at German Rheumatism Research Centre.

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  • Andrei Kruglov is PhD student at the Faculty of Bioengineering and Bioinformatics, Moscow State University and at German Rheumatism Research Centre.

    Anna Kuchmiy is a graduate student at Moscow Medical University. She has done research project at the Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow.

    Sergei Grivennikov received his PhD in molecular biology in 2004 from the Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow. He is currently a postdoctoral scientist at the University of California San Diego. He studies the role of cytokines in immune regulation and carcinogenesis.

    Alexei Tumanov received his MD from Russian State Medial University in 1996. He did his training at Engelhardt Institute of Molecular Biology, Moscow, and in US at National Cancer Institute and The Jackson Lab. He received his PhD in molecular biology at Engelhardt Institute of Molecular Biology, Moscow in 2003, focusing on LT and TNF cytokines in organization of secondary lymphoid organs. In 2004 he joined The University of Chicago, Department of Pathology, working on TNF family members in pathogenesis of human diseases. His interests include mechanisms of liver injury and regeneration, lipid metabolism and homeostasis of lymphoid organs.

    Dmitry Kuprash received his PhD and DSc degrees in molecular biology in 1994 and in 2006, respectively, from the Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow. He did his postdoctoral training in 1994-1997 at the National Cancer Institute, Frederick, Maryland, USA. He is currently a research group leader at the Engelhardt Institute, working on transcriptional regulation in immune system and on immunological recognition of human tumor-associated antigens.

    Sergei Nedospasov is Professor and Head of Laboratory of Molecular Immunology, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow. He has received both his PhD and DSc from that Institute, and was initially trained there with G. Georgiev and A. Varshavsky. He then did postdoctoral study with B. Hirt at ISREC in Lausanne, and has been head of research groups at NCI-Frederick (USA) and German Rheumatism Research Centre (Germany). S. Nedospasov is Associate Member of the Russian Academy of Sciences, Howard Hughes Medical Institute International Research Scholar, and the recipient of Helmholtz-Humboldt Award.

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