The IκB kinase (IKK) and NF-κB:: key elements of proinflammatory signalling

NF-kappa B is a heterodimeric transcription factor that plays a key role in inflammatory and immune responses. In nonstimulated cells, NF-kappa B dimers are maintained in the cytoplasm through interaction with inhibitory proteins, the I kappa Bs. In response to cell stimulation, mainly by proinflammatory cytokines, a multisubunit protein kinase, the I kappa B kinase (IKK), is rapidly activated and phosphorylates two critical serines in the N-terminal regulatory domain of the I kappa Bs. Phosphorylated I kappa Bs are recognized by a specific E3 ubiquitin ligase complex and undergo polyubiquitination which targets them for rapid degradation by the 26S proteasome. NF-kappa B dimers, which are spared from degradation, translocate to the nucleus to activate gene transcription. There is strong biochemical and genetic evidence that the IKK complex, which consists of two catalytic subunits, IKK alpha and IKK beta, and a regulatory subunit, IKK gamma, is the master regulator of NF-kappa B-mediated innate immune and inflammatory responses. In the absence of IKK gamma, which normally connects IKK to upstream activators, no IKK or NF-kappa B activation can occur. Surprisingly, however, of the two catalytic sub units, only IKK beta is essential for NF-kappa B activation in response to proinflammatory stimuli. The second catalytic subunit, IKK alpha, plays a critical role in developmental processes, in particular formation and differentiation of the epidermis.