TNF Tolerance in Monocytes and Macrophages: Characteristics and Molecular Mechanisms

Figure 3

Inhibition of NF-κB-associated signaling during high-dose-induced TNF tolerance. The signaling complex at the TNFR1 consists of tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD), TNF receptor-associated factor 2 (TRAF2), and RIP1. Via RIP-associated K63-linked polyubiquitin chains (blue dots), other proteins are recruited, especially the IKK complex (consisting of NF-κB essential modulator (NEMO), IKKα, and IKKβ) and the TGF-β-activated kinase (TAK) 1/TAK 1 binding protein (TAB) 2/3 complex. In high-dose TNF preincubated cells, IKK phosphorylation is inhibited by A20 presumably via noncatalytic binding of NEMO, induction of RIP degradation by K48-polyubiquitination (purple dots), and/or hydrolyzation of K63 polyubiquitins on several signaling proteins. A20-mediated restriction of IKK activity is supported by ABIN1 and CYLD and results in modulated IκBα proteolysis: a, during pre-incubation, an increased IκBα turnover leads to lower IκBα levels; b, following restimulation, no further decrease of IκBα levels occurs.