The interleukin (IL-1) receptor is a critical component in mediating the highly inflammatory responses of IL-1, which affects nearly every cell type. We have recently demonstrated that the activation of the transcription factor NF-kappaB depends not only upon the previously characterized IRAK pathway, but also a novel independent pathway involving IL-1 receptor tyrosine phosphorylation and recruitment and catalytic activation of phosphatidylinositol 3-kinase (PI3K). We propose to further study the involvement of this pathway in NF-kappaB activation and the activation of other transcription factors induced by IL-1. Additionally, we propose to investigate whether various signaling pathways mediated by the IL-1 receptor system converge with one or the other of the two distinct pathways.
Five specific aims are proposed: The first is designed to understand the detailed mechanism of NF-kappaB activation by PI3K focusing on the identification of the essential regions of the receptor cytoplasmic domain, the identity of the required critical tyrosine kinase, and the target sites on NF-kappaB and/or IkappaB required for activation.
The second aim will explore the relationship between PI3K and other IL-1 induced signals such as MAPK and the direct target of PI3K.
The third aim will investigate the molecular requirements for interactions among IL-1 receptor components including receptor heteromers, P13K, and IRAK. The fourth specific aim will identify regions of the receptor cytoplasmic domain and associated molecules involved in the activation of other IL-1-inducible transcription factors such as C/EBPbeta, Stat3, and the novel LPS/IL-1/IL-6 responsive LIL-Stat factor that we recently described. The identification of the recruitment sites for STAT factor activation and the target phosphorylation site on C/EBPbeta will be determined. The fifth aim will investigate the interplay between signal transduction pathways and the association of the IL-1 ligand with the receptor ectodomains as defined by IL-1 ligand mutations which we previously described as being capable of eliciting distinct signaling events. A new IL-1 mutation extends the earlier data arguing for an interplay between signal transduction pathways and the association of the IL-1 ligand with the receptor.
