Toll Comparative Pathway
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Toll Comparative Pathway
During inflammation, which results from tissue injury, infection, or autoimmune diseases, such as RA (Rheumatoid Arthritis), cells release inflammatory mediators that give rise to the symptoms of inflammation. These symptoms include vascular changes, such as increased blood flow, and extravasations and activation of leukocytes. Inflammation can be triggered when proteins known as TLRs (Toll-Like Receptors) detect specific patterns of molecules derived from bacteria or viruses. The TLRs , which are expressed on the surface of cells of the immune system, are at the front line in the fight against invading microorganisms. In response to TLR engagement, an intracellular signaling cascade is set off that leads to the production of intercellular messenger proteins called cytokines (Ref.1).

Toll-like members differ from those in the IL-1R (IL-1 Receptor Type-I) subgroup in that they contain LRRs (Leucine-Rich Repeats) instead of Ig (Immunoglobulin) domains. They include the mammalian TLRs (of which 10 have been described, termed TLR1 through TLR10), other insect members (including 18-Wheeler), and proteins involved in disease resistance in plants. In the developing Drosophila embryo, Toll drives the establishment of dorsoventral polarity. Spatzle is the ligand for Toll and is generated as a result of a protease cascade (Ref.2). Spatzle activation during immune challenge in Drosophila may require PGRP (Peptidoglycan Recognition Protein) and activation of the protease Persephone. Toll activates a protein kinase termed Pelle by interacting with adaptor proteins dMyD88, Tube and possibly dTRAF2 (Drosophila TNF-Alpha Receptor-Associated Factor-6). This pathway leads to the phosphorylation of Cactus, an I-KappaB (Inhibitor of Kappa Light Chain Gene Enhancer in B-Cells-Alpha) homologue which dissociates from the transcription factor Dorsal, allowing Dorsal to translocate to the nucleus and increase the expression of target genes involved in dorsoventral polarity. In adult Drosophila, Toll has an additional role in the response to infection. Toll activates another NF-kappaB (Nuclear factor-KappaB)/Rel family member, DIF (Dorsal-related Immunity Factor), which regulates the expression of antifungal peptides such as Drosomycin. Toll is not the receptor for microbial products, but is triggered by cleaved Spatzle, which is generated in a serpin controlled proteolytic cascade. Gram-negative and Gram-positive bacteria activate the Immune Deficiency Pathway through the putative transmembrane receptor PGRP-LC (Ref.3). The ultimate target of this pathway is Relish, an NF-kappaB/Rel family member closely related to mammalian p105. Relish is not inhibited by Cactus, but contains intrinsic inhibitory sequences in the form of ankyrin repeat domains. Activation of Relish depends on signal-induced endoproteolytic cleavage that frees the Rel homology domain, allowing for its translocation to the nucleus. dAPKC (Drosophila Atypical Protein Kinase-C) is also required for the stimulation of the Toll-signaling pathway, which activates DIF and Dorsal and controls the transcriptional activity of the Drosomycin promoter. Drosophila Ref(2)P (Refractory to sigma P) protein is the homologue of mammalian p62 and it binds to dAPKC. Its overexpression activates Drosomycin, and its depletion severely impairs Toll signaling. Both Ref(2)P and dAPKC are essential for Toll-induced Drosomycin expression, but they are not required for Cactus degradation. Other putative members of the Drosophila TIR (Toll/IL-1 Receptor) family include Tehao, 18-Wheeler, MstProx, Tollo, Tlr6, and Tlr4. Both Toll and Tehao are involved in the innate immune response, whereas the functions of the others remain to be determined. Toll homologues have also been described in other insects. The dipteran Clognia albipunctata and the beetle Tribolium castaneum both have Tolls (termed clToll and trToll, respectively) that regulate dorsoventral polarity (Ref.4). They probably also have a role in host defense.

The mammalian TLRs are expressed on macrophages and dendritic cells, which are primarily involved in innate immunity. At present, ligands for several of the TLRs , such as TLR2, TLR3, TLR4, TLR5, TLR6, and TLR9, have been identified. The most extensively characterized members are TLR2 and TLR4. TLR2 is required for responses to molecules from Gram-positive bacteria, and TLR4 is the long-sought-for signaling component for LPS (Lipopolysaccharide). A difference between fly and mammalian Toll is that LPS binds TLR4 directly, whereas in flies, Spatzle is generated in response to fungal products through the activation of Persephone and PRR (Pattern Recognition Receptor). On stimulation by specific microbial patterns, different TLRs trigger a common intracellular signaling cascade involving the adapter proteins MyD88, which is homologous to dMyD88, TRAF6 and the IRAK (IL-1R-Associated Kinase) proteins and is related to Pelle. This pathway eventually leads to the activation of cytokine-encoding genes (Ref.1). Upon activation, IRAK1 is phosphorylated, weakening its affinity for TollIP and making it more accessible for interaction with MyD88 and MAL (MyD88-Adaptor-Like), which is also known as TIRAP (Toll/IL-1 Receptor domain-containing Adaptor Protein). This secondarily phosphorylated form of IRAK1, called hyperphosphorylated IRAK1, is then released into the cytosol, where it interacts with the soluble TRAF6. The interaction with TRAF6 results in NF-KappaB activation. A novel protein linking TRAF6 to MEKK1 (MAP/ERK Kinase Kinases-1) has been described and is termed ECSIT (Evolutionarily Conserved Signaling Intermediate In Toll Pathways). Among IRAK family members, IRAK4 is the one with a protein sequence most similar to Drosophila Pelle. TRAF6 is the only TRAF family member to participate in both TNF and TLR signal transduction (Ref.5). It interacts with TAB2 (TAK1 Binding Protein-2), and this complex activates TAK1 (TGF-Beta-Activated Kinase-1). TAK1 then serves as a branch point, leading to activation of the I-KappaB complex and NF-KappaB, and the upstream kinases MEKK1 that activate p38 and JNK (c-Jun N-terminal kinase). When phosphorylated, I-KappaB dissociates from NF-KappaB, allowing NF-KappaB to translocate to the nucleus and increase expression of inflammatory and immune response genes. I-KappaB is a homologue of Cactus. Mammalian NF-KappaB is a family (NF-KappaB/Rel) that includes members homologous to Dorsal. This signaling pathway, starting with the TIR domain, is thus used in two different contexts to alter gene expression (Ref.6).

The TLR super family has emerged as an important determinant for inflammation and host defense. The conserved TIR domain, which defines the family, is evolutionarily ancient, possibly having arisen in prokaryotes, but certainly emerging in the common unicellular ancestor to plants and animals. In mammals, its importance can be seen in the critical role played by TLRs in the host response to bacteria (Ref.6).