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

Key Points

  • 19 ligands and 29 receptors that belong to the tumour-necrosis factor (TNF) superfamily have been identified.

  • At the cellular level TNF-superfamily members promote either apoptosis, proliferation, survival or differentiation.

  • The main signals transduced by the TNF-superfamily members include activation of nuclear factor-κB (NF-κB), JUN N-terminal kinase, p38 mitogen activated protein kinase and ERK1/ERK2.

  • Members of the TNF superfamily mediate haematopoiesis, immune surveillance, tumour regression and protection from infection.

  • Members of the TNF superfamily mediate inflammation, autoimmune diseases, rheumatoid arthritis, tumour metastasis, septic shock and osteoporosis.

  • TNF and its inhibitors have been approved as therapeutics.

Abstract

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.

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Figure 1: A diagrammatic representation of the ligands of the TNF superfamily and their receptors.
Figure 2: Cellular signalling pathways leading to activation of the main cellular responses by members of the TNF superfamily.
Figure 3: The structures of different TNF receptor-associated factors.
Figure 4: The balance between life and death mediated by TNF-superfamily members.
Figure 5: The main physiological and pathological effects linked to members of the TNF superfamily.
Figure 6: Present and future therapeutics.

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Acknowledgements

This research was supported by The Clayton Foundation for Research, by the Department of Defense of the US Army Breast Cancer Research Program and by the National Institutes of Health. I would like to thank Y. Takeda, A. Bharti, U. Bhardwaj and S. Shishodia for assistance with the graphics, U. Gaur and L. Ford for help in preparation of the manuscript and W. Pagel for a careful review of the manuscript.

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DATABASES

LocusLink

4-1BB

APRIL

BAFF

BAFFR

BCMA

CD27

CD30

CD30L

CD40

CD40L

CD95

CD95L

DCR1

DCR2

DCR3

DR4

DR5

DR6

EDA

EDAR

GITRL

HVEM

IAP1

IKKα

IKKβ

IKKγ

LT

LTβR

MEKK3

OPG

OX40

RANKL

RELT

RIP

SOCS3

TACI

TNF

TNFR1

TNFR2

TRADD

TRAF1

TRAF2

TRAF5

TRAF6

TRAIL

TRAILR1

TROY

TWEAK

VEGI

FURTHER INFORMATION

Bharat Aggarwal's lab

Glossary

SYSTEMIC LUPUS ERYTHEMATOSUS

(SLE). A disease of unknown origin in which tissues and cells are damaged by the deposition of pathogenic antibodies and immune complexes. Patients generally have abnormal B- and T-cell functions.

SJOGREN'S SYNDROME

(SS). An autoimmune disease characterized by diffuse lymphoid-cell infiltrates in the salivary and lacrimal glands, resulting in dry eyes and mouth due to insufficient secretion.

GRAFT-VERSUS-HOST DISEASE

(GVHD). Tissue damage in a recipient of allogeneic transplanted tissue (usually a bone-marrow transplant) that results from the activity of donor cytotoxic T cells that recognize the recipient's tissue as foreign. GVHD varies markedly in severity, but can be life threatening in severe cases. Typically, damage to the skin and gut mucosa leads to clinical manifestations.

IMMUNE-PRIVILEGED SITE

Immune-privileged sites are areas in the body with a decreased immune response to foreign antigens, including tissue grafts. These sites include the brain, eye, testis and uterus.

OSTEOPETROSIS

A hereditary bone disease with intense positive balance of body calcium. Autosomal recessive osteopetrosis is a rare, fatal disease characterized by the accumulation of excessive bone mass due to defective bone resorption. The pathogenesis of osteopetrosis is controversial. Defects in osteoblast–osteoclast interactions, incorrect differentiation of osteoclasts, abnormal contact between osteoclasts and the extracellular matrix, and abolished signalling can occur in this disease.

OSTEOPOROSIS

A condition that involves loss of bone due to an increase in the number of osteoclasts.

CANALE-SMITH SYNDROME

(CSS). An inherited disease characterized by massive lymphadenopathy, hepatosplenomegaly and systemic autoimmunity to erythrocytes and platelets.

AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME

(ALPS). ALPS is characterized clinically by chronic non-malignant lymphoproliferation and autoimmunity, and is caused by a genetic defect in apoptosis. Most patients with ALPS have heterozygous mutations in the CD95 gene.

OSTEOBLASTS

Cells that are responsible for the formation of bone.

OSTEOCLASTS

Cells that are responsible for bone resorption. They are rare cells with only 2–3 cells seen per 1 mm3 of bone. However, the loss of function in osteoclasts, problems with their differentiation and decrease in their number lead to bone osteosclerosis/osteopetrosis. Conversely, an increase in their number or function induces bone osteoporosis, indicating that osteoclasts have a pivotal role in bone homeostasis.

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Aggarwal, B. Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 3, 745–756 (2003). https://doi.org/10.1038/nri1184

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