Figure 5.

A proposed model of IRAK4 regulation of TLR7/8 signaling pathway in human monocytes is shown. Ligation of endosomal TLR7 and/or TLR8 by R848 leads to cytoplasmic assembly of the myddosome and autophosphorylation of IRAK4. Inflammatory cytokine production is induced by a signaling cascade including TAK1 and IKKβ that results in phosphorylation, nuclear translocation, and transcription mediated by IRF5 (right). At the same time, an as yet unidentified signaling cascade (left, dashed line) that requires IRAK4 scaffolding activity but not IRAK4 kinase activity but is independent of TAK1 and IKKβ, induces translocation of NFκB to the nucleus. Binding of both NFκB and IRF5 to the promoters of inflammatory cytokines is required for transcription.