The I kappa B kinase (IKK) and NF-kappa B: key elements of proinflammatorysignalling

NF-kappa B is a heterodimeric transcription factor that plays a key role in inflammatory and immune responses. In nonstimulated cells, NF-kappa B dime rs are maintained in the cytoplasm through interaction with inhibitory prot eins, the I kappa Bs. In response to cell stimulation, mainly by proinflamm atory cytokines, a multisubunit protein kinase, the I kappa B kinase (IKK), is rapidly activated and phosphorylates two critical serines in the N-term inal regulatory domain of the I kappa Bs. Phosphorylated I kappa Bs are rec ognized by a specific E3 ubiquitin ligase complex and undergo polyubiquitin ation which targets them for rapid degradation by the 26S proteasome. NF-ka ppa B dimers, which are spared from degradation, translocate to the nucleus to activate gene transcription. There is strong biochemical and genetic ev idence that the IKK complex, which consists of two catalytic subunits, IKK alpha and IKK beta, and a regulatory subunit, IKK gamma, is the master regu lator of NF-kappa B-mediated innate immune and inflammatory responses. In t he 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 activati on in response to proinflammatory stimuli. The second catalytic subunit, IK K alpha, plays a critical role in developmental processes, in particular fo rmation and differentiation of the epidermis.