TLR signal transduction pathways. (a) Signaling through TLR4 by bacterial LPS. TLR4 forms a complex with LBP, MD2, and CD14. When LPS binds TLR4, two adaptor complexes are recruited. The MyD88-dependent pathway activates IRAKs eventually leading to activation of TAK1 that leads to activation of transcription factor NF-κB and stimulates the MAPK pathways for transcription factor AP-1 activity. The TRIF-dependent pathway occurs within endosomes and activates RIP1, also resulting in TAK1 activation. Through TRAF3, IKKi and TBK1 are activated leading to the activation of transfer transcription factor IRF-3. (b) Signal through TLR3 by nucleic acids occurs within endosomes. When the receptor is occupied, TLR3 alone binds TRIF without TRAM. RIP1 is activated leading to the same subsequent events as those during TLR4 signaling. TRIF also activates IKKi and TBK1 leading to transcription factor IRF-3 activation, but involves TRAF6, not TRAF3. TLR: Toll-like receptor; LPS: lipopolysaccharide; LBP: LPS-binding protein; MD2: myeloid differentiation-2 protein; MyD88: myeloid differentiation primary response 88; TIR: Toll/interleukin-1 receptor; TIRAP: TIR-containing adaptor protein; TRIF: TIR domain-containing adaptor-inducing interferon-β; TRAM: TRIF-related adaptor molecule; IL: interleukin; IRAK: IL-1R-associated kinases; TNF: tumor necrosis factor; TRAF: TNF receptor-associated factors; TBK1: TANK-binding kinase-1; MAPK: mitogen-activated protein kinase; RIP1: receptor-interacting serine/threonine-protein kinase 1; TAK1: tumor growth factor-β-activated kinase 1; IKKi: inducible IκB kinase-I; IRF-3: interferon regulatory factor-3; AP-1: activator protein-1; NF-κB: nuclear factor-κB.