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-1beta from the naturally-occuring receptor antagonist. Signaling studies have focused primarily on the ability of IL-1 to transduce the activation of the transcription factor, NF-kappaB, 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 IkappaB molecule at two serines that precedes the proteolytic degradation of this inhibitor and the release of active NF-kappaB. The recent characterization of an IL-1 receptor associated kinase (IRAK) and a continuous molecular path between this kinase and that which directly phosphorylates IkappaB 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-kappaB 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-kappaB 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.[1]References
- The interleukin 1 receptor: ligand interactions and signal transduction. Auron, P.E. Cytokine Growth Factor Rev. (1998) [Pubmed]
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