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Unformatted text preview: Review Article Toll-like receptors in innate immunity Kiyoshi Takeda 1 and Shizuo Akira 2,3 1 Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, 2 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University and 3 ERATO, Japan Science and Technology Agency, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan Keywords : adaptor, innate immunity, signal transduction, TIR domain, Toll-like receptor Abstract Functional characterization of Toll-like receptors (TLRs) has established that innate immunity is a skillful system that detects invasion of microbial pathogens. Recognition of microbial components by TLRs initiates signal transduction pathways, which triggers expression of genes. These gene products control innate immune responses and further instruct development of antigen-specific acquired immunity. TLR signaling pathways are finely regulated by TIR domain-containing adaptors, such as MyD88, TIRAP/Mal, TRIF and TRAM. Differential utilization of these TIR domain-containing adaptors provides specificity of individual TLR-mediated signaling pathways. Several mechanisms have been elucidated that negatively control TLR signaling pathways, and thereby prevent overactivation of innate immunity leading to fatal immune disorders. The involvement of TLR-mediated pathways in autoimmune and inflammatory diseases has been proposed. Thus, TLR-mediated activation of innate immunity controls not only host defense against pathogens but also immune disorders. Introduction Host defense against invading microbial pathogens is elicited by the immune system, which consists of two components: innate immunity and acquired immunity. Both components of immunity recognize invading microorganisms as non-self, which triggers immune responses to eliminate them. To date, both components have been characterized independently, and the main research interest in the immunology field has been confined to acquired immunity. In acquired immunity, B and T lymphocytes utilize antigen receptors such as immuno- globulins and T cell receptors to recognize non-self. The mechanisms by which these antigen receptors recognize foreign antigens have been intensively analyzed, and the major mechanisms, such as diversity, clonality and memory, have been well characterized. However, these receptors are present only in vertebrates, and accordingly we do not fully understand the mechanism for non-self recognition in less evolved organisms. In addition, the innate immune system in mammals has not been well studied. As a result, although mammalian innate immune cells such as macrophages and dendritic cells are known to be activated by microbial com- ponents (non-self) such as lipopolysaccharide (LPS) from Gram-negative bacteria, a receptor responsible for the re- cognition remained unknown....
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