Fig. 1

Poly(I:C) and poly-ICLC signaling through TLR-3, MDA-5 and RIG-I generates a pro-inflammatory and interferon response. Poly(I:C) and poly-ICLC bind either the endosomal receptor TLR-3, leading to recruitment of adaptor molecule TICAM1, or the cytoplasmic receptors MDA-5 or RIG-I, which signal through the mitochondrial MAVS adaptor protein. Downstream both TICAM1 and MAVS transduce similar signal pathways via TRAF3 and TRAF6, though with distinct emphasis. TRAF3 leads to TBK1-IKKε complex formation, which results in phosphorylation of an IRF3 dimer that will induce an IFN response via IRSE3. TRAF6, along with RIP1, complexes TAK1 with TAB2 and TAB3, activating MAPK to activate transcription factor AP-1. The TAK1 complex will also activates the IKKα/β/γ complex, allowing transcription of NFκB. Both AP-1 and NFκB results in pro-inflammatory cytokines and chemokines. Hence, poly(I:C) and poly-ICLC signaling result in an immunostimulatory response. AP-1, activator protein 1; IFN, interferon; IKKα/β/γ, inhibitor of NFκB kinase regulatory subunit α/β/γ; IL-12, interleukin-12; IRF3, IFN regulatory factor 3; ISRE-3, IFN-stimulated response element 3; MAPKs, mitogen-activated protein kinases; MAVS, mitochondrial antiviral signaling protein; MDA-5, melanoma differentiation-associated gene 5; NFκB, nuclear factor κ-light-chain-enhancer of activated B cells; Poly(I:C), polyinosinic:polycytidylic acid; Poly-ICLC, poly(I:C) stabilized with carboxymethylcellulose and poly-L-lysine; RIG-I, retinoic acid-inducible gene I; RIP1, receptor-interacting serine/threonine-protein kinase 1; TAB, TAK1-binding protein; TAK1, transforming growth factor β activated kinase 1; TBK1, TRAF family member associated NFκB activator binding kinase 1; TICAM1, TLR adaptor molecule 1; TLR-3, Toll-like receptor 3; TRAF; tumor necrosis factor receptor associated factor 3