Signaling to NF-kB by Toll-like receptors

Innate immunity is the first line of defense against invading pathogens. A family of Toll-like receptors (TLRs) acts as primary sensors that detect a wide variety of microbial components and elicit innate immune responses. All TLR signaling pathways culminate in activation of the transcription factor nuclear factor-kappaB (NF-kB), which controls the expression of an array of inflammatory cytokine genes. NF-kB activation requires the phosphorylation and degradation of inhibitory kB (IkB) proteins, which is triggered by two kinases, IkB kinase a (IKKa) and IKKb. In addition, several TLRs activate alternative pathways involving the IKK-related kinases TBK1 [TRAF family member-associated NF-kB activator (TANK) binding kinase-1] and IKKi, which elicit antiviral innate immune responses. Here, we review recent progress in our understanding of the role of NF-kB in TLR signaling pathways and discuss potential implications for molecular medicine.