Figure 2

TLR signal transduction pathways. All TLR proteins utilize the adapter protein MyD88 to activate a signaling pathway leading to the activation of MAP kinases and the transcription factor NF-κB in a TRAF-6-dependent manner. These signaling events culminate in expression of the pro-inflammatory cytokines IL-1β and TNF-α. TLR4 uses an additional adapter molecule, called TIRAP or Mal, to induce the expression of IL-6 and IFN-β. Via an autocrine/paracrine mechanism, IFN-β engages the type I IFN receptor (IFNAR), which leads to the activation of the Jak and Tyk kinases. These kinases phosphorylate the transcription factor STAT1 at tyrosine 701 and serine 727, thus allowing STAT1 to translocate to the nucleus. Nuclear STAT1, together with NF-κB, activates the STAT1-dependent genes inducible nitric oxide synthase (iNOS) and IFN-γ-inducible protein (IP-10). The + symbols indicate that the two contributing signal transduction pathways must be triggered concomitantly in order to get gene activation.