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A Toll-like Receptor Recognizes Bacterial DNA

 



A Toll-like Receptor Recognizes Bacterial DNA

 

Toll-like receptor family plays crucial roles in innate immunity

The recognition of invading pathogen by host immune cells is a critical step for host defense in the multicellular organisms. Mammals have developed two types of immune system, innate and acquired immune system. The acquired immunity is based on lymphocytes with a huge repertoire of receptors that are generated through gene rearrangements such as B cell receptors and T cell receptors. On the other hand, a limited number of germline-encoded receptors are involved in the recognition of microorganisms in innate immunity (1). In order to detect many kinds of infectious agents, the innate immune system specifically recognizes structural patterns of microbial components, that are conserved among a wide variety of microorganisms. These structural patterns are referred as pathogen associated molecular patters (PAMPs), and include lipopolysaccharide (LPS), peptidoglycan (PGN), bacterial lipoproteins (BLP), mannans, bacterial DNA containing the CpG motif and so on (2). These PAMPs are essential for survival of microbes and are not expressed on the host. Once macrophages (MΦ) and dendritic cells (DC) recognize the existence of invading microbes, they activate subsequent acquired immunity by antigen presentation to antigen-specific lymphocytes as well as produce inflammatory cytokines such as tumor necrosis factor (TNF) - α, Interleukin (IL) -6 and nitric oxide (NO).

Host organisms have developed a set of receptors that can recognize specifically PAMPs. As one of these receptors, Toll-like receptor (TLR) family has been well studied (3). TLR family is originally identified as homologues of Drosophila Toll protein (4). Drosophila Toll is involved in not only the establishment of dorsoventral axis in the early embryogenesis but also immune response to fungal infection in the adult. Toll and TLR family are characterized as a type I transmembrane protein with leucine-rich repeats (LRR) in the extracellular domain and a cytoplasmic Toll/interleukin (IL)-1 receptor homology (TIR) domain. So far, ten members of human TLR are identified. Biological functions of some TLR family members have been revealed (Fig. 1); TLR4 is responsible for the recognition of LPS and TLR2 is indispensable for that of PGN and BLP (3). Recently, it has been reported that TLR5 mediates the recognition of flagellin, one of principal components of bacterial flagella (5). Activation of TLRs induces recruitment of the adaptor protein MyD88 (myeloid differentiation factor 88) and sequential activation of signaling molecules such as IRAK (IL-1 receptor associated kinase) and TRAF6 (TNF receptor associated factor) (Fig. 1). Finally, transcription factors AP-1 (activating protein-1) and NF-κB (nuclear factor-κB) are activated and translocated to the nucleus, where they induce gene expression of cytokines such as IL-1β, IL-6, IL-12 and co-stimulatory molecules such as CD80 and CD86 (6).

 

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