TNF ligands and receptors – a matter of life and death

Abstract

It had been known for some time that tumour masses which had become contaminated by a bacterial infection would on occasion regress and disappear. It was thought that the bacteria were releasing a factor which would make the tumour necrotic and whither. This factor was termed tumour necrosis factor (TNF) (Old, 1985). It was not until more recent advances in immunology that it became clear that antigens from the bacterial invader (notably lipopolysaccharide LPS) were causing the release of the patient's own TNF which could cause the tumour regression. The hunt was on to isolate this TNF which could be used as a magic therapy to control cancer cell growth and persistence, plus enhance the academic understanding of the ways by which a cell could die. It was discovered that TNF and lymphotoxin (LT) were products from macrophages and lymphocytes that were capable of lysing many cell types including some tumour cells (Carswell et al., 1975; Granger et al., 1969). TNF was also found to be identical to the protein cachectin, which was known to be involved in the fever and muscle wastage seen in cancer patients (Beutler et al., 1985). Hence, the role TNF played in a range of physiological actions was important and the hunt was on to identify TNF and related molecules such as LT. Modern techniques have since allowed the isolation, characterization and cloning of the genes for TNF which is structurally related to LT plus an expanding family of TNF-like ligands (Table 1). These cytokine molecules include ligands such as Fas, CD40 and RANK which cause wide-ranging long-term cellular activities in cells such as differentiation, proliferation or death. Evolution has created this TNF superfamily of cytokines to control and manipulate the immune system, modulating processes such as haematopoiesis, antibody production, or short- and long-term immunity. It is only through its quirky tumour-killing characteristic that TNF cytokine was first identified and may still hold the key to effective tumour therapy. As the majority of information has been gained about TNF and it is the archetypal cytokine of the superfamily, displaying the greatest range of cellular actions, this review will focus on the molecular aspects and biological role of TNF signalling. Biochemically isolated in 1984, TNF has since been found to be a pleiotropic agent produced mostly by activated macrophages and monocytes, but also by many other cell types including B lymphocytes, T lymphocytes and fibroblasts. It is expressed as a 26 kDa transmembrane protein that can be cleaved by the metalloprotease TNF-α-converting enzyme (TACE) to release a 17 kDa soluble TNF form (Idriss & Naismith, 2000). TNF has also referred to as TNFα, cachectin or differentiation inducing factor (DIF) (Aggarwal, 2000). Its superfamily of nearly 20 different homologues including TNF-β (lymphotoxin-α), lymphotoxin-β, and other more specific ligands such as RANKL and TRAIL which are involved more particularly in bone tissue and lymphocyte processes. All the TNF receptor superfamily of ligands are thought form non-covalently-bound homo-trimers which are capable of becoming a secreted form (Figure 1). These TNF ligand are primarily designed for cell – cell contact transfer of signalling information between neighbouring cells, but cleavage into their soluble forms may allow more dispersed cytokine effects. TNF as well as causing necrotic cell death may also cause apoptotic cell death, cellular proliferation, differentiation, inflammation, tumourigenesis, and viral replication (Figure 2). TNF's primary role is in the regulation of immune cells, but is known to be heavily involved in pathogenic disorders such as rheumatoid arthritis, asthma, septic shock, irritable bowel disorder, haemorrhagic fever and cachexia (Locksley et al., 2001). TNF superfamily ligand-receptor interactions. TNF receptor-mediated cellular responses. Just as modern molecular techniques have identified a superfamily of TNF-like cytokine ligands, their receptor molecules consist of a superfamily of proteins that can be activated by one or more ligands (Table 2). TNF receptors are an family of proteins that consist of, to date, at least 27 members characterized by their repeated cysteine-rich extracellular sequence homology, and include LT receptor, Fas, CD40, the low affinity nerve growth factor receptor, TRAIL receptors, RANK and death or decoy receptors (Darnay & Aggarwal, 1999). Many of these members go by multiple names and are activated by specific ligands, however TNF only has the ability to bind two of these receptors which are also activated by LTα. TNF ligand achieves all its different cellular and pathological effects by its binding to either the TNFR1 or TNFR2 receptor subtype. They are single transmembrane glycoproteins with 28% homology mostly in their extracellular domain with both containing four tandemly repeated cysteine rich motifs. Their intracellular sequences are largely unrelated with almost no homolo