TLR-4, IL-1R and TNF-R signaling to NF-kappa B: variations on a common theme

Toll-like receptors (TLRs) as well as the receptors for tumor necrosis factor (TNF-R) and interleukin-1 (IL-1R) play an important role in innate immunity by regulating the activity of distinct transcription factors such as nuclear factor-kappa B (NF-kappa B). TLR, IL-1R and TNF-R signaling to NF-kappa B converge on a common I kappa B kinase complex that phosphorylates the NF-kappa B inhibitory protein I kappa B alpha. However, upstream signaling components are in large part receptor-specific. Nevertheless, the principles of signaling are similar, involving the recruitment of specific adaptor proteins and the activation of kinase cascades in which protein-protein interactions are controlled by poly-ubiquitination. In this review, we will discuss our current knowledge of NF-kappa B signaling in response to TLR-4, TNF-R and IL-1R stimulation, with a special focus on the similarities and dissimilarities among these pathways.