The intriguing biology of the tumour necrosis factor/tumour necrosis factor receptor superfamily: players, rules and the games

Abstract

The members of the tumour necrosis factor (TNF)/tumour necrosis factor receptor (TNFR) superfamily are critically involved in the maintenance of homeostasis of the immune system. The biological functions of this system encompass beneficial and protective effects in inflammation and host defence as well as a crucial role in organogenesis. At the same time, members of this superfamily are responsible for host damaging effects in sepsis, cachexia, and autoimmune diseases. This review summarizes recent progress in the immunobiology of the TNF/TNFR superfamily focusing on results obtained from animal studies using gene targeted mice. The different modes of signalling pathways affecting cell proliferation, survival, differentiation, apoptosis, and immune organ development as well as host defence are reviewed. Molecular and cellular mechanisms that demonstrate a therapeutic potential by targeting individual receptors or ligands for the treatment of chronic inflammatory or autoimmune diseases are discussed.

Figure 1

The TNF/TNFR superfamily. The TNF-related ligands are shown in blue and arrows indicate interactions with their receptors. The ectodomains of the TNFR superfamily are shown in grey with the appropriate number of CRDs. Death domains within the cytoplasmic domain are indicated as red cylinders. All other receptors bind TRAF adaptors for signal transduction.

Figure 2

(a)Signal transduction of TNFRI. After binding of TNF, TNFRI first recruits TNFR associated death domain (TRADD) as a platform adaptor and assembles alternative signalling complexes. One complex involves receptor interacting protein (RIP) and TNFR associated factor 2 (TRAF2) which links ligand induced signalling to the activation of the transcription factors NF-κB and AP1. Another signalling complex is formed dependant on the internalization of activated TNF/TNFRI complexes (TNF receptosomes). During endocytosis FADD and caspase 8 are recruited to form the death inducing signalling complex (DISC) resulting in TNF-induced apoptosis. (b) Lymphotoxin beta receptor (LTβR) mediated NF-κB activation.Upon ligand induced activation of the LTβR two pathways are engaged. Activation of the IKK complex (IKKα, IKKβ, IKKγ/NEMO) and RelA controls the expression of inflammatory genes such as MIP-2, VCAM-1 and MIP-1β. The second pathway involves the activation of the NF-κB inducing kinase (NIK), which in turn activates IKKα for generating active p52 derived from its p100 precursor. Association of p52 with another partner (e.g. RelB) activates the transcription of genes implicated in lymphoid organogenesis and homeostasis such as SLC, BLC, ELC and BAFF.