The structure of each member of the TLR family of receptors provides important clues to how they function. All currently recognized TLRs are homologous with the interleukin-1 (IL-1) receptor, sharing an intracellular signaling domain, known as the Toll/IL-1R (TIR) domain (36) . A model that depicts the currently accepted mode of TLR signaling in leuko-cytes is shown in Figure 2 , in which the interaction with TLR4 and its cognate ligand lipopolysaccharide (LPS, endotoxin) is shown. The interaction of TLR4 with LPS leads to the activation of myeloid differentiation primary response protein 88 (MyD88)-dependent signaling, resulting in the induction of pro-inflammatory genes such as TNF-α, IL-1β, IL-6, and IL-10 (37-39) and MyD88-independent signaling cascades leading to activation of type-1 interferon (40 has a recent review) (38, 41) . MyD88-depedent signaling occurs as TIR domain-containing adapter protein (TIRAP/Mal) (42, 43) and MyD88 (44) (45) (46) interact with TLR4 and recruit IL-1 receptor-associated kinase (IRAK) family members IRAK1 and IRAK4 to the signaling heterocomplex consisting of TLR4, MyD88, and TIRAP (46) . Subsequent signaling occurs through tumor necrosis factor receptor-associated factor 6 (TRAF6)mediated (47) activation of transforming growth factor-β-activated protein kinase 1 (TAK1) (48) . TAK1 forms a complex with TAK1 binding proteins (TAB), TAB1 (49), TAB2 (50) , and TAB3 (51) . The TAK1/ TAB1/TAB2/TAB3 complex formation leads to the phosphorylation of IκB by IκB kinase (IκK) (52), initiating nuclear factorkappa B (NF-κB) signaling pathways and parallel activation of several mitogen-activated protein kinases (MAP-kinases) including c-Jun N-terminal kinase (JNK) (154) Viral proteins (106,143) Self DNA (155) Flagellin (58) Uric Acid (156) Bacterial DNA (148) Profilin (149) (53), p38 MAP-kinase (54) , and extracellular signal-regulated kinase (ERK) (55), ultimately resulting in pro-inflammatory gene induction (56, 57) . It is noteworthy that MyD88-dependent signaling is thought to be the predominant signaling pathway for TLR2 (41) , TLR5 (58), TLR7 (59) , and TLR9 (60,61). Figure 2 , TLR4 also may signal in the absence of MyD88. Evidence for this was demonstrated by Kawai et al., who described that the activation of NF-κB and MAP-kinases was reduced significantly, but not abolished, in MyD88-deficient mice (38) . The MyD88-independent signaling pathway proximally involves the activation of TRAM, a TIR-domain containing adapter molecule. TRAM associates with and activates TRIF, another TIR-domain containing adapter protein (62, 63) . TRIF then interacts with and activates TANKbinding kinase 1 (TBK1) and IKKε, two IκK homologs, which leads to the phosphorylation of IRF3 (64, 65) and translocation of IRF3 to the nucleus where it regulates the expression of various genes, including the type I IFN family of genes (66) . TRIF also interacts with TRAF6 and receptor interacting protein 1 (RIP), leading to the activation of NF-κB (67, 68) . Importantly, TLR3 signals mainly through the MyD88-independent, TRIFdependent pathway (62) .