The interleukin 1 receptor: Ligand interactions and signal transduction

The interleukin 1 (IL-1) receptor is a critical component in mediating the inflammatory responses of IL-1, which affect nearly every cell type. Recently, major inroads have been made toward understanding the mechanism by which IL-1 interacts with its receptor and activates signal transduction. The receptor-ligand association has been visualized by X-ray crystal structure analysis, revealing intimate details that distinguish IL-1 beta from the naturally-occurring receptor antagonist. Signaling studies have focused primarily on the ability of IL-1 to transduce the activation of the transcription factor, NF-kappa B, which is of central importance to inflammatory and immune responses. Virtually all of the effort has targeted the activation of a kinase which results in the phosphorylation of the inhibitory I kappa B molecule at two serines that precedes the proteolytic degradation of this inhibitor and the release of active NF-kappa B, The recent characterization of an IL-1 receptor associated kinase (IRAK) and a continuous molecular path between this kinase and that which directly phosphorylates I kappa B would seem to all but close the basic understanding of IL-1 receptor signal transduction, However, at least half of the IL-1-dependent NF-kappa B activation is independent of IRAK and uses a novel pathway involving the recruitment of phosphatidylinositol 3-kinase (PI3K) to a distinct site within the cytoplasmic domain of the IL-1 receptor. This novel pathway for NF-kappa B activation and the fact that other important transcription factors are also activated by an IL-1 receptor-dependent signal event, clearly defines additional mechanisms that influence inflammation. (C) 1998 Elsevier Science Ltd. All rights reserved.