Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents - Volume 4, Issue 6, 2005

Tumor necrosis factor (TNF) is the prototype member of a large family of cytokines that plays a crucial role in metazoan biology. Recent advances have identified TNF-like cytokines and their cognate receptors as critical mediators of many inflammatory diseases. The field of TNF biology is ever-expanding, with over 60,000 citations listed in the Pubmed, highlighting the progress of the field and its significance to human health in general. In this issue, we have attempted to provide a synopsis of recent advances in TNF biology, with a special emphasis on how TNF and its related cytokines contribute to the control of inflammatory processes. The reviews by Bixby et al. and Pham et al. summarize how two molecular events regulated by TNF, the control of cell death and NF kappa B activation, modulate the inflammatory process. The role of TNF in controlling inflammation is highlighted by human patients with genetic mutations in TNF receptor, a subject that is reviewed by Todd et al. Nikolov and Siegel reviewed the use of targeted therapies against TNF-mediated inflammatory diseases. Finally, Sedger provided a comprehensive review on how viruses have developed strategies to subvert TNF signaling and inflammation as a means to facilitate their survival and propagation within the infected host. It is our hope that these reviews will help the readers navigate through this rapidly expanding field of research.

Tumor necrosis factor (TNFα) is a pleiotropic cytokine that mediates diverse biological responses. In the immune system, TNFα facilitates many aspects of immune responses against pathogenic challenges. While TNFα plays a critical role in the immune defense against pathogens, hyper-activation of the TNFα signaling cascade often results in the development of inflammatory and autoimmune diseases. Examination of natural mutations in human and experimental mouse models that affect TNFα-TNF receptor interaction or their downstream signaling components confirm the importance of this cytokine/receptor pair in the inflammatory process and immunity. Blockade of TNF-TNF receptor interaction has been highly successful in treating several autoimmune diseases including rheumatoid arthritis and Crohn's disease. The pro-inflammatory effects of TNFα can be achieved through several distinct signaling mechanisms including the activation of NF-kB and programmed cell death. In this review, we discuss recent advances in our understanding of the mechanisms by which TNFα induces different forms of programmed cell death and the role they play in mediating the inflammatory response. Specifically, we discuss how the induction of a recently defined cell death pathway, programmed necrosis, by TNFα may contribute to the activation of innate immune responses and the inflammatory process.

NF-κB/Rel transcription factors are well-known for their roles in the regulation of inflammation and immunity. NF-κB also blocks programmed cell death (PCD) or apoptosis triggered by proinflammatory cytokine, tumor necrosis factor (TNF)α. Through transcriptional induction of distinct subsets of cyto-protective target genes, NF-κB inhibits the execution of apoptosis activated by this cytokine. This protective action is mediated, in part, by factors (such as A20, GADD45β, and XIAP) that downregulate the pro-apoptotic c-Jun-N-terminal (JNK) pathway. A suppression of reactive oxygen species (ROS), which are themselves major cell death-inducing elements activated by TNFα, is an additional protective function recently ascribed to NF-κB. This function of NF-κB involves an induction of mitochondrial antioxidant enzyme, manganese superoxide dismutase (Mn-SOD), and a control of cellular iron availability through upregulation of Ferritin heavy chain - one of two subunits of Ferritin, the major iron storage protein complex of the cell. An emerging view of NF-κB is that, while integrated, its actions in immunity and in promoting cell survival are executed through upregulation of distinct subsets of target genes. Thus, these inducible blockers of apoptosis may provide potential new targets to inhibit specific functions of NF-kB. In the future, this might allow for a better treatment of complex human diseases involving dysregulated NF-kB activity, including chronic inflammatory conditions and cancer.

Tumor necrosis factor receptor associated periodic syndrome (TRAPS) is a hereditary auto-inflammatory periodic fever syndrome associated with autosomal dominant ectodomain mutations in the 55kDa tumor necrosis factor receptor (TNFRSF1A). Over forty mutations in TNFRSF1A are associated with TRAPS. Plasma levels of soluble TNFRSF1A (sTNFRSF1A) are abnormally low in TRAPS patients, as is shedding of TNFRSF1A by some patients' leucocytes. It was hypothesised that a deficit in neutralisation of TNF by sTNFRSF1A in TRAPS might result in an increased sensitivity to the inflammatory effects of TNF. However, not all TRAPS-related TNFRSF1A mutations result in defective receptor shedding by leucocytes. We found that dermal fibroblasts, but not leucocytes, from TRAPS patients with C33Y mutation demonstrated reduced shedding of TNFRSF1A, and that shedding of both wild-type and mutant truncated TNFRSF1A from transfected cell lines was similar. It is unlikely that a defect in TNFRSF1A shedding fully explains the clinical features of TRAPS. We investigated the behaviour of TRAPS-related TNFRSF1A mutants compared with wildtype in transfected cell lines: the mutant forms of TNFRSF1A retained signalling functions, but showed abnormalities of intra-cellular trafficking and TNF binding suggestive of protein misfolding. The severity of the abnormalities were observed with different mutants correlated with the degree of penetrance and clinical severity. We hypothesise that aggregation and ligand-independent signalling of mutant TNFRSF1A may occur. The increased understanding of the genetic basis and pathophysiology of TRAPS has facilitated therapeutic advances in the clinical management of this condition, particularly the use of the TNF-neutralising agent etanercept.

In the last ten years, blockade of the cytokine TNF-alpha has emerged as a powerful new treatment for Rheumatoid Arthritis and related inflammatory disorders. However, differences in efficacy and side effect profiles amongst TNF antagonists have revealed important differences in their mechanisms of action. In addition, TNF is only one of more than nineteen related cytokines in the TNF superfamily, each of which plays a distinct role in immune system homeostasis and function. Blocking agents against other members of the TNF family are in development and hold promise in the treatment of Rheumatoid Arthritis and other autoimmune disorders. Recent progress in the understanding of the biology and effects of antagonizing therapeutically relevant TNF family members will be reviewed.

Apoptotic cell death can be triggered by death-inducing cytokines such and TNFα, Fas Ligand, and TRAIL, and death-receptors TNF-Rs, Fas, and TRAIL-Rs, or by mitochondrial-sensed events. The biochemical signalling pathways that lead from death receptors or mitochondria to the degradation of DNA and apoptotic cell death are wellcharacterized. Furthermore, it is clear that apoptotic cell death is important for the normal biology in all organisms. Apoptotic cell death is equally important in the context of virus infection such that the induction of apoptosis appears to be a generalised innate response to the insult of virus infection. As a consequence, viral-mediated regulation of apoptosis is crucial for the successful replication and survival of most viruses. For this reason viruses have evolved multiple strategies to subvert the apoptotic response. This review summarises the mechanisms by which viral gene products inhibit the production of TNFα, the interaction between TNFα and TNF-Rs, the expression of TNF-Rs, and inhibit virtually all aspects of TNF-R signalling, including TNF-R-mediated apoptosis and TNF-R-mediated proliferation and inflammation. Current Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents (2005). In press.

The white adipose tissue (WAT) represents the most important structure of the organism able to provide energy stores and heat insulation. Recently, its has been postulated that the adipose tissue can be considered as a complex, essential, and highly active metabolic and endocrine organ. Indeed, it is able to respond to different signals from the endocrine organs and from the nervous the immune systems. More recently, the adipose tissue has also been hypothesised to represent an "extension" of the immune system, for its capacity to contain immune cells, lymph nodes, thymus, but above all, for its ability to produce a series of cytokines and chemokines typical of the immune system (generally named adipokines). A better understanding of the immune and endocrine function of the adipose tissue will lead to the development of innovative therapeutic strategies in inflammatory disorders.

The nervous system and the immune system regulate a variety of essential, co-ordinated responses. Multiple anatomical and physiological connections exist between the CNS and the immune system and communication between these systems is relayed by multiple chemical messengers, ranging from small molecules such as nitric oxide to neuroendocrine peptides such as alpha melanocyte stimulating hormone to large proteins including cytokines and growth factors and their receptors. In the last few years, our knowledge about the interactions of the brain and immune system and the molecular framework that underpins these physiological interactions has advanced considerably.

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors with key metabolic roles in adipose tissue, liver and skeletal muscle. They are also expressed at significant levels in polymorphonuclear cells, monocyte/ macrophages, dendritic cells, T cells and B cells, suggesting that they may have a role in modulating the immune response. To date, evidence for such a role comes from numerous studies describing changes in gene expression within immunoregulatory cells in response to pharmacological PPAR ligands, reports of beneficial effects of PPAR agonists in auto-immune disease in rodents, and accelerated auto-immune disease in genetically modified rodents with reduced PPAR expression. Coupled with the knowledge that the PPARs may act as "lipid sensors", these data have added to the growing scientific awareness of links between nutritional status and immune function.

Histamine is a biogenic amine with a broad spectrum of activities in various physiological and pathological situations. Besides its well-characterised effects in allergic responses and in acute inflammation, histamine modulates the cytokine network, influencing T helper 1 and T helper 2 balance, and antibody isotype. In multiple sclerosis (MS), and its animal model of experimental autoimmune encephalomyelitis (EAE), there are several steps in the autoimmune attack against myelin of the central nervous system where histamine might play an important role. Indeed, blockade of specific histamine receptors has been proven to prevent early acute EAE by reducing encephalitogenic T helper 1 response and altering antigen presentation. A deeper understanding of the mechanisms by which histamine regulates the development and progression of EAE and MS might open new strategies for immune intervention.

Vitamin D receptor (VDR) agonists are well-known for their capacity to control calcium metabolism and to regulate growth and differentiation of many cell types. More recently, it has become clear that VDR agonists possess exquisite immunoregulatory properties, mostly by targeting dendritic cells and T cells. These properties have been exploited in the treatment of several Th1-mediated experimental autoimmune diseases, and a considerable body of work documents their beneficial effects in inhibiting the development of type 1 diabetes (T1D), a chronic-progressive autoimmune disease leading to the destruction of insulin-producing pancreatic β cells. This review analyzes the capacity of different VDR agonists to inhibit spontaneous T1D development in the non-obese diabetic (NOD) mouse, and shows that 1α,25-(OH)2-16,23Z-diene-26,27-hexafluoro-19-nor D3 (compound 6) is the most effective analog, among those tested, in delaying and reducing disease progression. Identified mechanisms of action underlying the efficacy of this VDR agonist in inhibiting T1D development in the NOD mouse are also reviewed.