Signalling pathways of the TNF superfamily: a double-edged sword

Nat Rev Immunol. 2003 Sep;3(9):745-56. doi: 10.1038/nri1184.


Two different tumour-necrosis factors (TNFs), first isolated in 1984, were found to be cytotoxic to tumour cells and to induce tumour regression in mice. Research during the past two decades has shown the existence of a superfamily of TNF proteins consisting of 19 members that signal through 29 receptors. These ligands, while regulating normal functions such as immune responses, haematopoiesis and morphogenesis, have also been implicated in tumorigenesis, transplant rejection, septic shock, viral replication, bone resorption, rheumatoid arthritis and diabetes; so indicating their role as 'double-edged swords'. These cytokines either induce cellular proliferation, survival, differentiation or apoptosis. Blockers of TNF have been approved for human use in treating TNF-linked autoimmune diseases in the United States and other countries.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Autoimmune Diseases / drug therapy
  • Autoimmune Diseases / immunology
  • Carrier Proteins / immunology
  • Humans
  • Ligands
  • Lymphotoxin-alpha / antagonists & inhibitors
  • Lymphotoxin-alpha / immunology*
  • Membrane Proteins / immunology
  • Mice
  • NF-kappa B / immunology
  • Receptors, Tumor Necrosis Factor / immunology*
  • Signal Transduction / immunology
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / immunology*


  • Carrier Proteins
  • Ligands
  • Lymphotoxin-alpha
  • Membrane Proteins
  • NF-kappa B
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha