Figure 2

(a) The MyD88-independent pathway. (b) Crosstalk between the MyD88-dependent and MyD88-independent pathways. The MyD88-independent pathway can lead to the activation of both IRF and NF-kB and the subsequent expression of IFNs and pro-inflammatory cytokines, respectively. The MyD88-independent pathway is initiated by TRAM and TRIF. After being recruited, TRIF interacts with TBK and IKK-ɛ to phosphorylate the transcription factor IRF3. TRIF can also interact with IRAK1 and IKK-ɛ to activate the transcription factor IRF7. Activated IRFs then translocate into nucleus, bind with DNA, and produce such antiviral molecules as IFN-β. In addition, TRIF can also promote MyD88-independent NF-κB activation in TLR4 signaling pathways. Similar to the MyD88-dependent pathway, TRIF recruits TRAF6 and activates TAK1 through ubiquitination-dependent mechanisms, which in turn activates the NF-κB and MAPK pathways. Moreover, TRIF also activates MyD88-independent NF-κB activation by recruiting RIP1. Thus, TRIF activates IRFs by interacting with TBK1 and IRAK1 and activates NF-κB by interacting with RIP1. Furthermore, RIP1 can interact with FADD, which initiates caspase cascades and then induces cell apoptosis. Gene names: IKK-ɛ, inhibitory κB (IκB) kinase ɛ; IRAK1, interleukin (IL)-1 receptor-associated kinase 1; IRF, IFN-regulatory factor; TANK, TRAF family member-associated NF-κB activator; TRIF, TIR-domain-containing adapter-inducing interferon-β; TLR4, Toll-like receptor 4