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.

(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.