MyD88-dependent and -independent signaling by IL-1 in neurons probed by bifunctional Toll/IL-1 receptor domain/BB-loop mimetics

Interleukin (IL)-1[beta] is a pluripotent proinflammatory cytokine that signals through the type-I IL-1 receptor (IL-1RI), a member of the Toll-like receptor family. In hypothalamic neurons, binding of IL-1[beta] to IL-1RI mediates transcription-dependent changes that depend on the recruitment of the cytosolic adaptor protein myeloid differentiation primary-response protein 88 (MyD88) to the IL-1RI/IL-1 receptor accessory protein (IL-1RAcP) complex through homomeric Toll/IL-1 receptor (TIR)--TIR interactions. Through design and synthesis of bifunctional TIR mimetics that disrupt the interaction of MyD88 with the IL-1RI/IL-1RAcP complex, we analyzed the involvement of MyD88 in the signaling of IL-1[beta] in anterior hypothalamic neurons. We show here that IL-1[beta]-mediated activation of the protein tyrosine kinase Src depended on a MyD88 interaction with the IL-1RI/IL-1RAcP complex. The activation of the protein kinase Akt/PKB depended on the recruitment of the p85 subunit of PI3K to IL-1RI and independent of MyD88 association with the IL-1RI/ IL-1RAcP complex. These bifunctional TIR-TIR mimetics represent a class of low-molecular-weight compounds with both an anti-inflammatory and neuroprotective potential. These compounds have the potential to inhibit the MyD88-dependent proinflammatory actions of IL-1[beta], while permitting the potential neuronal survival supporting actions mediated by the MyD88-independent activation of the protein kinase Akt. cytokine | interleukin | protein-protein interaction | inflammation