Signal transduction pathways activated by the IL-1 receptor family: ancient signaling machinery in mammals, insects, and plants

Interleukin-1 (IL-1) is a central regulator of the immune and inflammatory responses. Recently, significant advances have been made in the area of IL-1 receptors and IL-1 signal transduction. A family of proteins has been described that share significant homology in their signaling domains with the Type I IL-1 receptor (IL-1RI). These include the IL-1 receptor accessory protein (IL-1AcP), which does not bind IL-1 but is essential for IL-1 signaling; a Drosophila protein Toll; a number of human Toll-like receptors (hTLRs); the putative IL-18/IL-1-gamma receptor IL-1Rrp (IL-1 receptor-related protein); and a number of plant proteins. All appear to be involved in host responses to injury and infection. These homologies also extend to novel signaling proteins implicated in IL-1 action. Two IL-1 receptor-associated kinases, IRAK-1 and IRAK-2, which have homologs in Drosophila (Pelle) and plants (Pto), have been implicated in the activation of the transcription factor, nuclear factor kappaB (NF-kappaB). IRAK-1 has also been implicated in AP1 induction, Jun amino-terminal kinase (JNK) activation, and IL-2 induction. It recruits the adapter protein TRAF6 to the IL-1 receptor complex via an interaction with IL-1AcP. TRAF6 then relays the signal via NF-kappaB-inducing kinase (NIK) to two I-kappaB kinases (IKK-1 and -2), leading to NF-kappaB activation. Progress has also been made on other IL-1-responsive kinases, including JNK and p38 MAP kinase, with the latter having a role in multiple responses to IL-1. The remarkable conservation between diverse species indicates that the IL-1 system represents an ancient signaling machine critical for responses to environmental stresses and attack by pathogens.