Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey

Abstract

Although activity that induced tumor regression was observed and termed tumor necrosis factor (TNF) as early as the 1960s, the true identity of TNF was not clear until 1984, when Aggarwal and coworkers reported, for the first time, the isolation of 2 cytotoxic factors: one, derived from macrophages (molecular mass 17 kDa), was named TNF, and the second, derived from lymphocytes (20 kDa), was named lymphotoxin. Because the 2 cytotoxic factors exhibited 50% amino acid sequence homology and bound to the same receptor, they came to be called TNF-α and TNF-β. Identification of the protein sequences led to cloning of their cDNA. Based on sequence homology to TNF-α, now a total of 19 members of the TNF superfamily have been identified, along with 29 interacting receptors, and several molecules that interact with the cytoplasmic domain of these receptors. The roles of the TNF superfamily in inflammation, apoptosis, proliferation, invasion, angiogenesis, metastasis, and morphogenesis have been documented. Their roles in immunologic, cardiovascular, neurologic, pulmonary, and metabolic diseases are becoming apparent. TNF superfamily members are active targets for drug development, as indicated by the recent approval and expanding market of TNF blockers used to treat rheumatoid arthritis, psoriasis, Crohns disease, and osteoporosis, with a total market of more than US $20 billion. As we learn more about this family, more therapeutics will probably emerge. In this review, we summarize the initial discovery of TNF-α, and the insights gained regarding the roles of this molecule and its related family members in normal physiology and disease.

Figure 1

Roles of various members of the TNF superfamily in inflammation, cellular proliferation, apoptosis, and morphogenesis. All members of the TNF superfamily exhibit pro-inflammatory activity, in part through activation of the transcription factor NF-κB (full red circle); OX40L, CD40L, CD27L, APRIL, and BAFF exhibit proliferative activity in part through activation of various mitogen-activated kinases (sky blue); TNF-α, TNF-β, FasL, and TRAIL control apoptosis (bluish-green); and EDA-A1, EDA-A2, TNF-α, FasL, and TRAIL regulate morphogenesis (green).

Figure 2

Timeline for the discovery of various members of the TNF superfamily, their receptors, and the receptor-associated adaptor proteins.

Figure 3

Autocrine, paracrine, cell to cell, and reverse signaling pathways for TNF-α. Ligands, such as TNF-α, are expressed as both transmembrane and in soluble forms. The transmembrane form of the ligand appears to mediate therapeutic effects, but soluble ligand is linked to pathologic effects of TNF-α. Ligands, such as TNF-β, lack the transmembrane domain and thus are expressed only as a soluble protein. TNF-α, made by tumor cells, acts primarily through TNFR1 in an autocrine and paracrine manner. There are also examples of reverse signaling through TNF-α when it binds to its receptor.

Figure 4

Cell signaling pathways activated by TNF. TNFR1 activation leads to recruitment of intracellular adaptor proteins (TRADD, FADD, TRAF, and RIP), which activate multiple signal transduction pathways. TNFR sequentially recruits TRADD, TRAF2, RIP, TAK1, and IKK, leading to the activation of NF-κB; and the recruitment of TRADD, FADD, and caspase-8, leads to the activation of caspase-3, which in turn induces apoptosis. JNK is activated through the sequential recruitment of TRAF2, RIP, MEKK1, and MKK7. Exposure of cells to TNFα in most cases results in the generation of reactive oxygen species, leading to activation of MKK7 and JNK. The activation of ERK and p38MAPK is via TRADD, TRAF2, RIP, TAK1, and MKK3/6.

Figure 5

Various diseases that have been closely linked to TNF-α and members of its family.

Figure 6

Diseases caused by mutation of genes in members of the TNF superfamily, its receptors, and adaptor proteins. Red circle represents studies in human; and yellow circle, studies in mice. Asterisk (*) within yellow circle indicates diseases in dogs.