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      A comprehensive map of the toll-like receptor signaling network

      1 , 2 , 1 , 2 , 3 , a

      Molecular Systems Biology

      bow-tie structure, robustness, toll-like receptor

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          Abstract

          Recognition of pathogen-associated molecular signatures is critically important in proper activation of the immune system. The toll-like receptor (TLR) signaling network is responsible for innate immune response. In mammalians, there are 11 TLRs that recognize a variety of ligands from pathogens to trigger immunological responses. In this paper, we present a comprehensive map of TLRs and interleukin 1 receptor signaling networks based on papers published so far. The map illustrates the possible existence of a main network subsystem that has a bow-tie structure in which myeloid differentiation primary response gene 88 (MyD88) is a nonredundant core element, two collateral subsystems with small GTPase and phosphatidylinositol signaling, and MyD88-independent pathway. There is extensive crosstalk between the main bow-tie network and subsystems, as well as feedback and feedforward controls. One obvious feature of this network is the fragility against removal of the nonredundant core element, which is MyD88, and involvement of collateral subsystems for generating different reactions and gene expressions for different stimuli.

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          Most cited references 343

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          Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA.

          Interferons (IFNs) are critical for protection from viral infection, but the pathways linking virus recognition to IFN induction remain poorly understood. Plasmacytoid dendritic cells produce vast amounts of IFN-alpha in response to the wild-type influenza virus. Here, we show that this requires endosomal recognition of influenza genomic RNA and signaling by means of Toll-like receptor 7 (TLR7) and MyD88. Single-stranded RNA (ssRNA) molecules of nonviral origin also induce TLR7-dependent production of inflammatory cytokines. These results identify ssRNA as a ligand for TLR7 and suggest that cells of the innate immune system sense endosomal ssRNA to detect infection by RNA viruses.
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            Differential Roles of TLR2 and TLR4 in Recognition of Gram-Negative and Gram-Positive Bacterial Cell Wall Components

            Toll-like receptor (TLR) 2 and TLR4 are implicated in the recognition of various bacterial cell wall components, such as lipopolysaccharide (LPS). To investigate in vivo roles of TLR2, we generated TLR2-deficient mice. In contrast to LPS unresponsiveness in TLR4-deficient mice, TLR2-deficient mice responded to LPS to the same extent as wild-type mice. TLR2-deficient macrophages were hyporesponsive to several Gram-positive bacterial cell walls as well as Staphylococcus aureus peptidoglycan. TLR4-deficient macrophages lacked the response to Gram-positive lipoteichoic acids. These results demonstrate that TLR2 and TLR4 recognize different bacterial cell wall components in vivo and TLR2 plays a major role in Gram-positive bacterial recognition.
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              Missing pieces in the NF-kappaB puzzle.

              The regulation of the transcription factor NF-kappaB activity occurs at several levels including controlled cytoplasmic-nuclear shuttling and modulation of its transcriptional activity. A critical component in NF-kappaB regulation is the IkappaB kinase (IKK) complex. This review is focused on recent progress as well as unanswered questions regarding the regulation and function of NF-kappaB and IKK.
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                Author and article information

                Journal
                Mol Syst Biol
                Molecular Systems Biology
                1744-4292
                2006
                18 April 2006
                : 2
                : 2006.0015
                Affiliations
                [1 ]The Systems Biology Institute, Tokyo, Japan
                [2 ]Department of Fundamental Science and Technology, Keio University, Tokyo, Japan
                [3 ]Sony Computer Science Laboratories Inc., Tokyo, Japan
                Author notes
                [a ]The Systems Biology Institute, Suite 6A, M31 6-31-15 Jingumae, Shibuya, Tokyo 150-0001, Japan. Tel.: +81 3 5468 1661; Fax: +81 3 5468 1664; E-mail: kitano@ 123456symbio.jst.go.jp
                Article
                msb4100057
                10.1038/msb4100057
                1681489
                16738560
                Copyright © 2006, EMBO and Nature Publishing Group
                Page count
                Pages: 1
                Categories
                Review Article

                Quantitative & Systems biology

                robustness, bow-tie structure, toll-like receptor

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