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Keywords:

  • tumour necrosis factor;
  • signal transduction;
  • inflammation;
  • infection;
  • arthritis;
  • therapy

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Production of TNF
  5. TNF signal transduction
  6. Regulation of TNF receptors
  7. Cell biological effects of TNF in the inflammatory response
  8. Physiological roles of TNF
  9. Therapeutic agents for TNF blockade
  10. Summary
  11. Acknowledgements
  12. Teaching materials
  13. References
  14. Supporting Information

TNF was originally described as a circulating factor that can cause necrosis of tumours, but has since been identified as a key regulator of the inflammatory response. This review describes the known signalling pathways and cell biological effects of TNF, and our understanding of the role of TNF in human disease. TNF interacts with two different receptors, designated TNFR1 and TNFR2, which are differentially expressed on cells and tissues and initiate both distinct and overlapping signal transduction pathways. These diverse signalling cascades lead to a range of cellular responses, which include cell death, survival, differentiation, proliferation and migration. Vascular endothelial cells respond to TNF by undergoing a number of pro-inflammatory changes, which increase leukocyte adhesion, transendothelial migration and vascular leak and promote thrombosis. The central role of TNF in inflammation has been demonstrated by the ability of agents that block the action of TNF to treat a range of inflammatory conditions, including rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease and psoriasis. The increased incidence of infection in patients receiving anti-TNF treatment has highlighted the physiological role of TNF in infectious diseases. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Production of TNF
  5. TNF signal transduction
  6. Regulation of TNF receptors
  7. Cell biological effects of TNF in the inflammatory response
  8. Physiological roles of TNF
  9. Therapeutic agents for TNF blockade
  10. Summary
  11. Acknowledgements
  12. Teaching materials
  13. References
  14. Supporting Information

Tumour necrosis factor (TNF, also known as TNFα) was identified in 1975 as an endotoxin-induced glycoprotein, which caused haemorrhagic necrosis of sarcomas that had been transplanted into mice 1. Human tumour necrosis factor was cloned in 1985 2, and recombinant TNF was shown to induce the haemorrhagic necrosis of transplanted methylcholanthrene-induced sarcomas in syngeneic mice. TNF has since been implicated in a diverse range of inflammatory, infectious and malignant conditions, and the importance of TNF in inflammation has been highlighted by the efficacy of anti-TNF antibodies or administration of soluble TNF receptors (TNFRs) in controlling disease activity in rheumatoid arthritis and other inflammatory conditions.

Production of TNF

  1. Top of page
  2. Abstract
  3. Introduction
  4. Production of TNF
  5. TNF signal transduction
  6. Regulation of TNF receptors
  7. Cell biological effects of TNF in the inflammatory response
  8. Physiological roles of TNF
  9. Therapeutic agents for TNF blockade
  10. Summary
  11. Acknowledgements
  12. Teaching materials
  13. References
  14. Supporting Information

TNF is produced predominantly by activated macro- phages and T lymphocytes as a 26 kDa protein, pro-TNF, which is expressed on the plasma membrane, where it can be cleaved in the extracellular domain by the matrix metalloproteinases, which result in the release a soluble 17 kDA soluble form. Both membrane-associated and soluble TNFs are active in their trimeric forms, and the two forms of TNF may have distinct biological activities. TNFα converting enzyme (TACE, also known as ADAM-17) mediates release of TNF from the cell surface 3, but is involved in processing several cell-membrane associated proteins, including TNF receptors, which are released by its action to produce soluble froms that can neutralize the actions of TNF 4. TACE may therefore be either pro- or anti-inflammatory, depending on whether it acts on an effector (eg macrophage) or target (eg endothelial) cell, releasing ligand or receptors, respectively.

TNF is not usually detectable in healthy individuals, but elevated serum and tissue levels are found in inflammatory and infectious conditions 5, 6 and serum levels correlate with the severity of infections 7, 8. Although cells of the monocyte/macrophage lineage are the main source of TNF in inflammatory disease, a wide range of cells can produce TNF, including mast cells, T and B lymphocytes, natural killer (NK) cells, neutrophils, endothelial cells, smooth and cardiac muscle cells, fibroblasts and osteoclasts.

TNF signal transduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Production of TNF
  5. TNF signal transduction
  6. Regulation of TNF receptors
  7. Cell biological effects of TNF in the inflammatory response
  8. Physiological roles of TNF
  9. Therapeutic agents for TNF blockade
  10. Summary
  11. Acknowledgements
  12. Teaching materials
  13. References
  14. Supporting Information

TNF signal transduction pathways are complex and still not fully understood. Regulation of the transcription factor NF-κB is a key component of TNF signal transduction, but large-scale physical mapping in combination with loss of function analysis using RNA interference recently identified 221 molecular associations and 80 previously unknown interactors involved in modulation of the TNF–NF-κB pathway alone 9.

All known responses to TNF are triggered by binding to one of two distinct receptors (Figure 1), designated TNFR1 (also known as TNFRSF1A, CD120a, p55) and TNFR2 (also known as TNFRSF1B, CD120b, p75), which are differentially regulated on various cell types in normal and diseased tissue 10. The extracellular, ligand-binding domains of TNF receptors contain cysteine-rich subdomains, characteristic of members of the nerve growth factor/TNF receptor gene family. In contrast, the intracellular domains of the two receptors show no sequence homology and are devoid of intrinsic enzyme activity, and activate distinct signal transduction pathways by recruitment of cytosolic proteins through specific protein–protein interaction domains 11. The ability of TNFR1 and TNFR2 to interact with both identical and unrelated molecules may explain their shared and diverse functions. Based on cell culture work and studies with receptor knockout mice, both the pro-inflammatory and the programmed cell death pathways that are activated by TNF, and associated with tissue injury, are largely mediated through TNFR1. The consequences of TNFR2 signalling are less well characterized, but TNFR2 has been shown to mediate signals that promote tissue repair and angiogenesis.

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Figure 1. Signalling pathways leading to the main cellular responses of TNF. Soluble TNF receptors or monoclonal anti-TNF antibodies, which prevent TNF interacting with its receptors and activating these pathways, can be used to treat inflammatory disease

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TNFR1 signals by recruitment of TNFR-associated-death-domain protein (TRADD) 12. TNFR1 is a type I transmembrane protein, which in resting cells is predominantly sequestered in the Golgi apparatus, from where it can be mobilized to the cell surface.

The significance of the Golgi pool of TNFR1 molecules is unclear. One hypothesis is that it may act as a reservoir to increase surface receptor expression density, thereby sensitizing cells to the actions of TNF. There is precedence for this idea in smooth muscle cells, in which the TNF receptor family member Fas localizes predominantly to the Golgi, from where it can be translocated to the cell surface, thereby sensitizing cells to Fas ligand-induced killing 13.

Surface-expressed TNFR1 exist as trimers associated through pre-ligand assembly domains (PLADs) 14, which reside within the membrane distal cysteine-rich domain. In unstimulated receptors the cytoplasmic domain is pre-associated with a cytoplasmic protein designated silencer of death domain (SODD) 15. SODD is thought to prevent constitutive signalling of TNFR1, although mice congenitally deficient in expression of the sodd gene display normal TNFR1 signalling 16. Both TNFR1 and SODD contain ‘death domains’ (DDs), which are protein motifs that interact with other DDs. SODD uses its DD to bind to the DD contained within the cytosolic portion of TNFR1, preventing signalling. TNF binding to TNFR1 may result in the release of SODD, allowing binding of a different DD-containing cytoplasmic protein, TNFR-associated DD protein (TRADD). TRADD initiates signalling by recruiting two additional proteins, receptor interacting protein-1 (RIP-1), a serine/threonine kinase which binds to TRADD through its own DD 17, and TNFR-associated factor-2 (TRAF-2) an E3 ubiquitin ligase 18) that does not contain a DD. Within minutes this complex is internalized 12, and the TRADD–RIP-1–TRAF2 complex is released from TNFR1. Inhibitors of this process can interfere with signalling 19, 20.

Subsequent signalling events involve recruitment and activation of different mitogen activated protein kinase kinase kinases (MAP3Ks)]. RIP-1 is thought to mediate recruitment of MEKK-3 and transforming growth factor-beta (TGFβ)-activated kinase (TAK)1, which in turn, activate the β-subunit of the inhibitor of κB (IκB)] kinase (IKK) complex 21, 22, leading to phosphorylation of IκB proteins, signalling IκB ubiquitination and proteosome-mediated degradation. Cystosolic IκB proteins from a complex with the NF-κB family transcription factors, masking nuclear localization signals within NF-κB, and IκB degradation allows NF-κB to enter the nucleus and initiate gene transcription.

TRAF2 can also contribute to NF-κB activation, both through binding of the IKK complex 23 and through recruitment of inhibitor of cellular apoptosis proteins (cIAP)-1 and -2. cIAPs have caspase inhibitors that also have ubiquitin protein ligase (E3)] activity and can participate in IκB degradation 24. The TRADD–RIP-1–TRAF-2 complex can also recruit apoptosis-signalling kinase-1 (ASK-1)], a MAP3K that associates with TRAF2 25 and activates MAP2Ks, including MEK-4 and -6 26, 27. These MEKs phosphorylate and activate c-Jun N-terminal kinases (JNKs) and p38 MAPKs. Activated JNKs phosphorylate the amino terminal region of c-Jun, a subunit of the transcription factor activating protein 1 (AP-1). Phosphorylation of the amino terminal region of c-Jun by JNK is essential for interactions of this protein with cAMP-response-element-binding-protein-binding protein [CBP]/p300 and gene transcription. TNFR1 can also interact with FAN (factor associated with neutral SMase activation) to activate neutral sphingomyelinase, which can generate ceramide from the breakdown of plasma membrane sphingomyelin 28 and initiate apoptosis through the mitochondrial pathway 29.

In addition to mediating cell survival and pro-inflammatory signals through NF-κB and AP-1, TNFR1 can also initiate cell death signalling pathways. This involves the binding of Fas-associated DD protein (FADD) to TRADD and the subsequent recruitment of pro-caspase 8 by the TRADD–FADD complex. Autocatalytic activation of bound pro- caspase 8 releases activated caspase 8, which initiates apoptotis through cleavage and activation of pro-caspase 3. The recruitment and activation of pro-caspase 8 can be inhibited by cFLIP, and elevated levels of cFLIP induced by NF-κB activation may prevent the activation of this death pathway 30. TNFR1 activates other signalling responses that are less clearly defined at a molecular level. These include activation of the ras–raf–MEK1–ERK1,2 pathway 31 and phosphatidylinositol-3 kinase (PI3K), which phosphorylates the membrane lipid phosphatidylinositol 4.5 diphosphate (PIP2), converting it to phosphatidylinositol 3, 4, 5 triphosphate (PIP3). PIP3 activates PDK-1, an enzyme that phosphorylates the kinase Akt, and also activates PDK-2, a complex containing mammalian target of rapamycin (mTOR), rictor and SAPK-interacting protein (Sin)1, which is also involved in activation of Akt 32. ERK-1, -2 and Akt are generally associated with cell survival and proliferation 33.

The signalling pathways initiated by TNFR2 are less clearly defined, but TNFR2 appears to signal both shared and opposing effects to TNFR1. TNFR2 lacks an intracellular death domain, but can interact with TRAFs. TRAF1 was initially identified as a novel 45 kDa protein that could be co-immunoprecipitated with human TNFR2 transfected into the murine interleukin-2-dependent cytotoxic T cell line CT6, and also from CT6 cell lysates by a GST fusion protein containing the region of human TNFR2 required for signal transduction 34. At the same time, TRAF2 was identified as a novel 56 kDa protein by using the yeast two-hybrid system to detect proteins that interact directly with the cytoplasmic domain of hTNFR2. Despite the co-immunoprecipitation studies, only a very weak interaction between TRAF1 and the cytoplasmic domains of hTNFR2 or mTNFR2 could be detected using the two-hybrid system. This seeming contradiction was reconciled by the observations that a strong heteromeric interaction occurred between TRAF1 and TRAF2, and that TRAF1 and TRAF2 could form homo- and heterotypic dimers. Consequently, TRAF1 and TRAF2 can associate with the cytoplasmic domain of TNFR2 as a heterodimeric complex in which only TRAF2 contacts the receptor directly. However, despite inherent strong TRAF2 binding activity, ligand-dependent activation of TNFR2 does not appear to deliver strong TRAF2-dependent signals, and TNFR2 has since been found to have a TRAF2-binding site with high inherent signalling capabilities, designated T2bs-N, together with a carboxyl-terminal TRAF2-binding site designated T2bs-C that prevents the delivery of signals from T2bs-N 35. This may provide a mechanism for diverting TRAF2 from TNFR1 via T2bs-C without inducing TRAF2-mediated signals. Binding of TNF to TNFR2 can also limit signalling by c-IAP1-dependent ubiquination and degradation of TRAF2 and ASK1, terminating MAP3K signalling 36.

TNFR2 can also activate endothelial/epithelial tyrosine kinase (Etk), a cytosolic kinase implicated in cell adhesion, migration, proliferation and survival, independently of TRAF2. Etk is a novel regulator of epithelial cell junctions and mediates the TNF-induced phosphatidylinositol 3-kinase (PI3K)–Akt angiogenic pathway in vascular endothelial cells through Etk-mediated cross-talk with vascular endothelial growth factor receptor 2 (VEGFR2) 37. TNF activates Etk through TNFR2 in a TRAF2-independent manner. TNFR2 associates with an inactive form of Etk in a ligand-independent fashion through the C-terminal 16-amino acid sequence of TNFR2 and multiple domains of Etk. TNF is thought to induce a conformational change in TNFR2 that triggers unfolding of the closed, inactive form of Etk. In endothelial cells, TNF induces assembly of a trimolecular complex containing TNFR2, Etk and vascular endothelial growth factor receptor 2 (VEGFR2, also known as KDR or flk-1). Within this complex, there is a coordinate reciprocal phosphorylation of Etk and VEGFR2, resulting in PI3K activation 37. The appearance of phosphorylated Etk is indicative of TNFR2 signalling 38.

The utilization of different signalling mechanisms by TNFR1 and TNFR2 is consistent with the ability of each receptor to signal distinct biological responses in cultured cells. Ligation of TNFR1 is both necessary and sufficient to induce cytotoxic and pro-inflammatory TNF responses, whereas TNFR2 may promote cell activation, migration or proliferation. Under certain circumstances, TNFR2 may contribute to TNFR1 responses, particularly at low concentrations of TNF 39, consistent with the notion of ‘ligand passing’, in which TNFR2 captures TNF and passes it to TNFR1 40. Cooperation between the receptors may also be explained by the ligand-induced formation of TNF receptor heterocomplexes 41.

Regulation of TNF receptors

  1. Top of page
  2. Abstract
  3. Introduction
  4. Production of TNF
  5. TNF signal transduction
  6. Regulation of TNF receptors
  7. Cell biological effects of TNF in the inflammatory response
  8. Physiological roles of TNF
  9. Therapeutic agents for TNF blockade
  10. Summary
  11. Acknowledgements
  12. Teaching materials
  13. References
  14. Supporting Information

Most cell lines and primary tissues co-express both TNF receptors, although TNFR2 is preferentially expressed on cells of haematopoietic lineage 42. TNF receptor types show a much more limited pattern of cellular expression in vivo, and are highly regulated by ischaemic or inflammatory tissue injury. For example, normal kidney appears largely devoid of TNFR2 molecules, and TNFR1 molecules are essentially confined to microvascular and glomerular endothelial cells. This restricted protein distribution is supported by in situ hybridization studies for receptor-encoding mRNA. In kidney allografts undergoing rejection or ischaemic injury, TNFR1 is lost from the endothelium and there is new expression of TNFR2 in renal tubular epithelial cells. This regulated expression of TNF receptors, which is recognized to occur in a wide range of tissues, is likely to result from changes in both the rate of synthesis and shedding of receptors.

A number of stimuli, including TNF, IL-1, IL-10 and tissue plasminogen activator, increase expression of TNFR2 through transcriptional activation, whereas TNFR1 is more commonly down-regulated by these stimuli 43–45. The possibility of differential synthesis of the receptors is further supported by characterization of their promoter regions. The 5′-regulatory region of TNFR1 possesses features of a housekeeping promoter 46, 47. The inducibility of TNFR2 is supported by analysis of its promoter region, which has a cAMP-response element and consensus elements for a number of transcription factors, including NF-κB, AP-1, IRF-1 and GAS 42. An additional factor that is known to influence expression of TNF receptors is shedding from the cell surface. TNF-binding proteins, later characterized as soluble forms of the two molecular species of cell surface TNF receptors, were first purified from normal human urine 48. Inflammatory mediators are known to induce shedding of TNFR1 from endothelial cells 49, 50, and nitric oxide and hydrogen peroxide have been implicated in the activation of a metalloproteinase involved in shedding of TNFR1 51. The TNF receptor-associated periodic syndrome (TRAPS) is an autoinflammatory syndrome characterized by episodes of fevers, with severe localized inflammation 52. TRAPS is associated with heterozygous mutations in the extracellular domain of TNFR1, which are associated with receptor misfolding, an inability to form soluble receptors and altered signalling 53.

Cell biological effects of TNF in the inflammatory response

  1. Top of page
  2. Abstract
  3. Introduction
  4. Production of TNF
  5. TNF signal transduction
  6. Regulation of TNF receptors
  7. Cell biological effects of TNF in the inflammatory response
  8. Physiological roles of TNF
  9. Therapeutic agents for TNF blockade
  10. Summary
  11. Acknowledgements
  12. Teaching materials
  13. References
  14. Supporting Information

Although TNF receptors are differentially expressed on a wide range of cells and tissues, many of the pro-inflammatory effects of TNF can be explained on the basis of TNF's effects on vascular endothelium and endothelial leukocyte interactions. In response to TNF, endothelial cells promote inflammation by displaying, in a distinct temporal, spatial and anatomical pattern 54–56, different combinations of adhesion molecules for leukocytes, including E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) 57, 58. In combination with the release of chemokines (including IL-8, MCP-1 and IP-10) 59, these responses lead to recruitment of different populations of leukocytes independent of antigen recognition. In addition, many of the classical features of inflammation can be produced by local effects of TNF on endothelial cells. TNF-induced expression of cyclo-oxygenase 2 can increase EC production of vasodilatory PGI2 resulting in vasodilatation 60, causing ‘rubor’ and ‘calor’ through increased local blood flow. ‘Tumour’ can result from TNF-mediated increased vascular permeability, allowing the increased trans-endothelial passage of fluid and macromolecules to create oedema. In addition, TNF-induced expression of pro-coagulant proteins, such as tissue factor, and down-regulation of anticoagulant protein, such as thrombomodulin TNF, can cause intravascular thrombosis 61.

Physiological roles of TNF

  1. Top of page
  2. Abstract
  3. Introduction
  4. Production of TNF
  5. TNF signal transduction
  6. Regulation of TNF receptors
  7. Cell biological effects of TNF in the inflammatory response
  8. Physiological roles of TNF
  9. Therapeutic agents for TNF blockade
  10. Summary
  11. Acknowledgements
  12. Teaching materials
  13. References
  14. Supporting Information

One of the major biological roles of TNF is in the host defence to bacterial, viral and parasitic infections. Physiologically, TNF is important for the normal response to infection, but inappropriate or excessive production can be harmful. TNF was originally identified as an endotoxin lipopolysaccharide (LPS)-induced humoral mediator of murine cachexia, the syndrome of anorexia, weight loss and protein wasting that complicates cancer and chronic infection and inflammation 62. TNF was confirmed as the principal mediator of the lethal effect of Escherichia coli-derived endotoxin by demonstrating that passive immunization of mice with rabbit anti-serum to TNF protected mice from its lethality 63. Baboons passively immunized with a neutralizing monoclonal anti-TNF antibody and subsequently infused with a lethal dose of live E. coli were protected against shock, vital organ dysfunction, persistent stress hormone release and death 64. However, although a recombinant, soluble fusion protein that combines an extracellular portion of the human TNF receptor and the Fc portion of IgG (TNFR : Fc) neutralizes TNF and prevents death in animal models of bacteraemia and endotoxaemia, in patients with septic shock, treatment with TNFR : Fc did not reduce mortality, and higher doses appeared to be associated with increased mortality 65.

The importance of TNF as a modulator of the host response to infection has been confirmed by studies using TNF receptor-deficient mice. Mice deficient in TNFR1 are resistant to lethal dosages of either lipopolysaccharides or Staphylococcus aureus enterotoxin B, but have severely impaired clearance of the intracellular bacterium Listeria monocytogenes and readily succumb to this infection 66, 67. The activity of TNF in endotoxin-induced lethal shock and innate resistance to Listeria appears to be independent of TNFR2 68. TNF has since been shown to be essential for the formation and maintenance of granulomas, which limit dissemination of Listeria and other infections, including mycobacteria 69, and a number of granulomatous infections have been reported in association with the use of TNF antagonists to treat human inflammatory disease 70.

Evidence also supports a key role for TNF in parasitic and viral infections. TNF levels are increased in the serum of children with uncomplicated Plasmodium falciparum malaria, and markedly increased in children with a fatal outcome from cerebral malaria, leading to speculation that increased TNF production is a normal host response to P. falciparum infection, but that excessive levels of production may predispose to cerebral malaria and a fatal outcome 8.

TNF appears to be central for the ICAM-1-dependent recruitment of mononuclear cells and microvascular damage that occurs in cerebral malaria 71. Anti-TNF therapy inhibits fever in cerebral malaria 72 but does not improve survival 73. Support for a role of TNF in host defences against viruses has been provided by the existence of viruses encoding TNF-binding proteins in their genome 74. Furthermore, side-effects typically associated with viraemia, including fever, rigors, headache and fatigue, were observed in early trials of TNF in cancer patients 75, 76. Indeed, although initially described as a tumouricidal agent, toxicity has limited the role of TNF as a chemotherapeutic agent for cancer. Furthermore, TNF may under some circumstances contribute to carcinogenesis by promoting proliferation, invasion and metastasis of tumour cells 77. However, isolated limb perfusion with TNF is of value in palliating patients with metastatic sarcoma and melanoma 78, 79, providing tumour control and limb salvage for the short survival of patients, and isolated hepatic perfusion with TNF has been used in patients with hepatic metastases 80.

Although TNF blockade failed to be of benefit in severe sepsis, the trials that were undertaken paved the way for its use in chronic inflammatory diseases such as rheumatoid arthritis, which in turn has highlighted the physiological roles of TNF in sepsis and malignancy.

Therapeutic agents for TNF blockade

  1. Top of page
  2. Abstract
  3. Introduction
  4. Production of TNF
  5. TNF signal transduction
  6. Regulation of TNF receptors
  7. Cell biological effects of TNF in the inflammatory response
  8. Physiological roles of TNF
  9. Therapeutic agents for TNF blockade
  10. Summary
  11. Acknowledgements
  12. Teaching materials
  13. References
  14. Supporting Information

Three drugs, Humira (adalibumab), Remicade (infliximab) and Enbrel (etanercept) are currently licensed as TNF-blocking agents and used to treat rheumatoid arthritis and other inflammatory diseases, including ankylosing spondylitis and Crohn's disease. Etanercept is a recombinant human soluble fusion protein in which TNFR2 is coupled to the Fc portion of IgG. Infliximab is a human–murine chimeric IgG1 monoclonal anti-TNF antibody. Adalibumab is a human anti-human TNF antibody produced by phage display. Other agents in clinical development have used PEGylation to couple a large molecular weight polyethylene glycol molecule to the TNF antagonist, with the aim of prolonging the half-life. PEG–sTNFR1 is a pegylated form of soluble TNFR1, and CDP-870 is a pegylated Fab of the humanized anti-TNF antibody CDP-571.

Different anti-TNF therapies may have different binding and pharmacokinetic profiles. The chimeric monoclonal antibody infliximab may be a more potent inhibitor of TNFR2 signalling than the TNFR2–Fc fusion protein entarecept. Infliximab binds transmembrane TNF with higher avidity, forming more stable complexes and more effectively inhibiting the actions of transmembrane TNF than entarecept 81. Transmembrane TNF is superior to soluble TNF in activating TNFR2 in various systems, including T cell activation, thymocyte proliferation and granulocyte/macrophage colony-stimulating factor production 82. Thus, under certain conditions infliximab may be more effective at blocking signalling through TNF2 than etanercept.

The US Food and Drug Administration (FDA) has reported certain serious, but uncommon, adverse events with all three approved anti-TNF agents (http://www.fda.gov/ohrms/dockets/ac/03/briefing/3930B1_01_B-TNF.Briefing.htm), including serious bacterial infections, tuberculosis and certain opportunistic infections, demyelinating syndromes and systemic lupus erythaematosus-like reactions. In controlled studies of TNF blockade, more cases of lymphoma occurred among patients receiving the agents than among control patients, and in open-labelled uncontrolled studies the rate of malignancies in the treatment group was several times higher than would be expected in the general population. The available data suggest that these adverse reactions may be related to TNF blockade and therefore represent class effects of these agents.

Rheumatoid arthritis

Rheumatoid arthritis is a chronic autoimmune inflammatory disorder affecting approximately 1% of the population, characterized by inflammation of synovial tissue, leading to progressive damage, erosion of adjacent cartilage and bone and chronic disability. The inflammation is associated with accumulation of inflammatory cells, predominantly T cells and macrophages, but also B cells, plasma cells and dendritic cells. There is synovial hyperplasia and angiogenesis is a prominent feature 83. Many pro-inflammatory cytokines, including IL-1, IL-6, TNF and GM-CSF, are produced within the inflamed joint 84.

Support for a dominant role of TNF was provided by a number of in vitro and in vivo studies. Production of a range of pro-inflammatory cytokines by cultured cells from the joints of patients with rheumatoid arthritis can be down-regulated by a neutralizing antibody to TNF 85, 86. Neutralizing TNF with either anti-TNF antibody or a recombinant soluble TNF receptor ameliorates joint disease in a murine model of collagen-induced arthritis 87–89. Deleting TNF AU-rich elements (AREs) from the mouse genome resulted in profound temporal and spatial deregulation of TNF production, characterized by the persistent accumulation and decreased rates of decay of the mutant TNF mRNA. This deregulation resulted in overexpression of TNF and the development of chronic inflammatory arthritis and inflammatory bowel disease 90.

An open Phase I/II clinical trial of a murine-human chimeric neutralizing monoclonal antibody to TNF in 20 patients with active rheumatoid arthritis demonstrated that the treatment was safe and well tolerated and resulted in significant clinical and laboratory improvements 91. The efficacy of anti-TNF treatments in rheumatoid arthritis was subsequently confirmed in randomized controlled trials, which established that methotrexate and anti-TNF treatment have a synergistic effect, and demonstrated that long-term treatment is feasible 92–98, although loss of response may occur in about half of patients during the first year 99.

Inflammatory bowel disease

TNF immunoreactivity is increased the lamina propria in intestinal specimens from patients with Crohn's disease and ulcerative colitis 100, 101, and mice overexpressing TNF develop a Crohn's disease-like inflammatory bowel disease 90.

Infliximab has been shown to be effective in inducing remission, and an effective maintenance therapy for patients with Crohn's disease with and without fistulas 102, 103. A randomized controlled trial demonstrated that the humanized anti-TNF antibody CDP571 was an effective for treatment of patients with moderate to severe Crohn's disease 104, but subsequent studies showed that CDP571 is not effective for long-term treatment of unselected patients with moderate to severe Crohn's disease 105.

A systemic review of randomized controlled trials of TNF-blocking agents in patients with active Crohn's disease found that infliximab and CDP571, but not etanercept, may be effective in inducing remission 106.

The role of TNFα-blocking agents in ulcerative colitis is less clear, and recent studies have yielded conflicting results. A systematic review concluded that in patients with moderate to severe ulcerative colitis whose disease is refractory to conventional treatment using corticosteroids and/or immunosuppressive agents, infliximab is effective in inducing clinical remission, inducing clinical response, promoting mucosal healing and reducing the need for colectomy, at least in the short term 107.

Ankylosing spondylitis

Ankylosing spondylitis is an inflammatory arthritis that predominantly affects the spine and sacroiliac joints. It occurs more commonly in patients with Crohn's disease. TNF has been detected in the sacro-iliac joints of patients with ankylosing spondylitis 108, particularly in early active disease 109, and elevated serum levels of TNF correlate with disease activity 110.

A randomized, double-blind trial of etanercept showed that treatment with etanercept for 4 months resulted in rapid, significant and sustained improvement in patients with ankylosing spondylitis 111. Subsequent studies have confirmed the efficacy and safety of etanercept in patients with active ankylosing spondlitis over 2 years of continuous treatment 112, 113, and have shown that etanercept is effective in patients with early onset ankylosing spondylitis before the age of 18 114.

Infliximab is also an effective agent in patients with active ankylosing spondylitis, for inducing and maintaining remission and readministration to treat relapse after discontinuation of long-term therapy 115, 116.

Psoriasis

Psoriasis is an inflammatory skin disorder, in which an inflammatory cell infiltrate is associated with hyperkeratotic lesions, giving rise to typical psoriatic plaques. TNF, TNFR1 and TNFR2 are upregulated in dermal blood vessels in involved skin from patients with psoriasis 117, 118.

Randomized trials showed that infliximab resulted in a rapid and significant improvement in psoriatic plaques 119, 120. Up to one-third of patients with psoriasis develop an inflammatory arthritis, which can affect both spinal and peripheral joints. Early studies suggested a role for etanercept in the treatment of psoriatic arthritis, and subsequent studies have shown that infliximab, etanercept and adalimumab are all effective treatments for the dermatological and articular manifestations of psoriasis 121–124.

Disease of the central nervous system

In the central nervous system, TNF is produced primarily by microglia and astrocytes in response to a wide range of pathological processes, including infection, inflammatory disease, ischaemia and traumatic injury 125. However, TNF has been shown to have both harmful and beneficial effects in the injured brain 126. Inhibition of TNF ameliorates ischaemic brain injury in mice 127, whereas mice lacking TNF are highly susceptible to experimental autoimmune encephalomyelitis, and treatment with TNF dramatically reduces disease severity 128. TNF-mediated protection against experimental autoimmune encephalomyelitis does not require TNFR1, although TNFR1 appears to be necessary for detrimental effects of TNF, which occur during the acute phase of the disease 129. In contrast, TNFR2 has been shown to promote proliferation of oligodendrocyte progenitors and remyelination in a neurotoxicant murine model of demyelination 130. Neutralization of TNF failed to benefit patients with relapsing–remitting multiple sclerosis, and significantly increased exacerbations 131.

Cardiovascular disease

TNF has also been implicated in the pathogenesis of a number of cardiovascular diseases, including atherosclerosis, myocardial infarction, heart failure, myocarditis and cardiac allograft rejection, and vascular endothelial cell responses to TNF may underlie the vascular pathology in many of these conditions. However, clinical trials have demonstrated no clinical benefit of TNF blockade in congestive cardiac failure. This may be because TNFR1 and TNFR2 differentially regulate cardiac responses to TNF. In transgenic mice with TNF-induced cardiomyopathy, ablation of the TNFR2 gene exacerbates heart failure and reduces survival, whereas ablation of TNFR1 blunts heart failure and improves survival 132. In cardiac allografts either TNF receptor is capable of mediating a response that will culminate in graft arterial disease 133.

Patients with chronic inflammatory conditions such as rheumatoid arthritis have an increased incidence of cardiovascular disease. Inflammatory mediators, including TNF, have been implicated in this increased cardiovascular risk, and there is some evidence that anti-TNF therapy ameliorates this risk in patients with rheumatoid arthritis 134.

Respiratory disease

TNF has been implicated in the pathophysiology of many inflammatory lung diseases, including chronic bronchitis, chronic obstructive pulmonary disease, acute respiratory distress syndrome and asthma 135. In asthma, TNF has been implicated in airway inflammation and remodelling, and may play a role in bronchial hyper-responsiveness. Leukocytes from bronchiolar lavage of asthma patients have increased release of TNF 136, and inhaled TNF increases airway responsiveness in normal subjects and is associated with a pulmonary neutrophil infiltration, assessed by induced sputum. To date there are no randomized controlled trials of TNF blockade in asthma, but patients with asthma who received infliximab for rheumatoid arthritis have demonstrated a significant improvement, and an open label uncontrolled study of etanercept in 17 subjects with severe asthma demonstrated an improvement in asthma symptoms, lung function and bronchial hyper-responsiveness following 12 weeks of entanercept 137. A pilot study of patients with refractory asthma provided evidence for a role of TNF, and demonstrated a beneficial effects of etanercept on markers of asthma control 138.

Renal disease

TNF has been implicated in the pathogenesis of many renal diseases, including ischaemic renal injury, renal transplant rejection and glomerulonephritis, which is often part of a systemic vasculitis. In diseases associated with renal inflammation, different forms of TNF blockade vary in their efficacy and adverse effects, and these differences may be attributed to different effects on signalling though TNF receptor subtypes. In acute renal injury, TNFR2-mediated cell proliferation may be important for tubular cell regeneration 38, whereas in proliferative forms of glomerulonephritis, TNFR1-mediated cytotoxicity and inhibition of TNFR2-mediated cellular proliferation may be more desirable.

TNFR2 is essential for the development of renal injury in a model of immune complex glomerulonephritis induced by anti-GBM antibody, raising the possibility that selective blockade of TNFR2 may be a promising strategy for treatment of immune-mediated glomerulonephritis 139.

As discussed above, infliximab may be more effective at blocking signalling through TNFR2 than etanercept. In support of this, infliximab is an effective treatment for patients with refractory Wegener's granulomatosis 140, in which lymphocyte activation and glomerular cell proliferation are important in pathogenesis. In contrast, etanercept is not effective for the maintenance of remission in patients with Wegener's granulomatosis, and its use is associated with an increased incidence of solid tumours 141.

Other inflammatory diseases

As the potential role of TNF blockade has become clear, its successful use has been reported in an increasing number of inflammatory conditions. These include juvenile rheumatoid arthritis 142; therapy-resistant sarcoidosis, a multisystemic disorder characterized histologically by the presence of granulomatous inflammation 143–145; inflammatory myopa- thies 146; Behcet disease 147; and inflammatory eye disease 148.

Summary

  1. Top of page
  2. Abstract
  3. Introduction
  4. Production of TNF
  5. TNF signal transduction
  6. Regulation of TNF receptors
  7. Cell biological effects of TNF in the inflammatory response
  8. Physiological roles of TNF
  9. Therapeutic agents for TNF blockade
  10. Summary
  11. Acknowledgements
  12. Teaching materials
  13. References
  14. Supporting Information

Although the capacity of bacterial toxins to induce tumour regression was first described at the end of the nineteenth century, TNF was not identified as the tumouricidal agent until 1975. TNF was cloned in 1984, and the last two decades have seen how molecular and cellular biological techniques, combined with in vivo studies, have unravelled the complexity of TNF and its signalling pathways and the pathophysiological responses it triggers. This has led to an understanding of its key role in inflammatory disease and perhaps the most remarkable example of translational medicine, as scientists have collaborated with clinicians and the pharmaceutical industry to develop improved anti-inflammatory therapies. In turn, clinical studies are providing valuable insights into the mechanism of action of TNF, allowing the science to return to the laboratory to continue to address the many unanswered questions.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Production of TNF
  5. TNF signal transduction
  6. Regulation of TNF receptors
  7. Cell biological effects of TNF in the inflammatory response
  8. Physiological roles of TNF
  9. Therapeutic agents for TNF blockade
  10. Summary
  11. Acknowledgements
  12. Teaching materials
  13. References
  14. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Production of TNF
  5. TNF signal transduction
  6. Regulation of TNF receptors
  7. Cell biological effects of TNF in the inflammatory response
  8. Physiological roles of TNF
  9. Therapeutic agents for TNF blockade
  10. Summary
  11. Acknowledgements
  12. Teaching materials
  13. References
  14. Supporting Information

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path2287-PATH2287fig1.ppt195KFigure 1. Signalling pathways leading to the main cellular responses of TNF

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