Treatment of endotoxin-induced tissue damages by the negative regulation of TLR-mediated signal pathways

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Immunity is largely categorized into two types, adoptive immunity and innate immunity. As compared with innate immunity, acquired immunity has the diversity and the accuracy in its recognition of corresponding antigens based on the DNA rearrangement machineries and hypermutation properties that T cells and B cells selectively possess. Therefore, acquired immunity had been believed to he extremely sophisticated and ideal system for host defense. Innate immunity had been regarded to play a role only as the front line that would drop out after activation of the corresponding acquired immunity. In fact, innate immune constituents, such as dendritic cells(DCs) and macrophages, can promptly respond to microbes and their products without help from additional acquired immune responses, whereas acquired immunity takes long time to be able to exert its full immunological actions. However, recent intensive studies on signaling receptors in the innate immune system, in particular on toll-like rece … More ptors(TLRs), led us to notify its importance comparable to adaptive immunity. After microbial infection, antigen-presenting cells(APCs) composing innate immunity capture the microbial antigens. Simultaneously, the microbial products stimulate the APCs through their TLRs to undergo the appropriate maturation, which is represented by expression of chemokine receptors critical for translocation into the regional lymph nodes and of various co-stimulatory molecules essential for the appropriate activation of T helper cells. These APCs produce a variety of cytokines in response to the TLR ligands of the microbes as well. Unless they experience these biological events through their TLRs, these APCs cannot drive the activation or differentiation of antigen-specific T cells. In particular, certain cytokines, such as IL-12 and IL-18, produced by the APCs are required for the differentiation of naive helper T cells toward the effector cells to eradicate the microbes. Thus, the absence of innate immune responses render mammalian host highly susceptible to pathological organisms.Innate immunity is equipped with various signaling receptors including a TLR family (Janeway and Medzhitov,2002). TLR family consists of more than 10 members. Each member precisely recognizes corresponding molecular patterns associated with pathogens, and exerts its host defensive actions based on their ignorance of host-derived intact components. Indeed, the TLR-mediated signal pathways are essential for microbe expulsion at the early infectious phase. Unexpectedly and importantly, the signalings through TLRs are definitely required for the following activation of the acquired immunity. Lack of the TLR-mediated pathway sometimes causes immature T cell responses and failure in the development of memory T cells, presumably due to the absence of cytokine production and DC maturation and activation, which is normally induced by the activation of the TLR pathway and is required for those immunological events.Like in the case of autoimmunity associated with the dysregulated adaptive immunity, excessive activation of innate immunity causes diseases. It is well documented that the activation of innate immunity by pathogens occasionally causes fatal pathological alterations via aberrant induction of cytokines. Both innate and acquired immune systems complete their proper actions via cognate cellular interactions and cytokine catch bowl. Therefore, it is quite important for homeostatic immune responses to regulate the innate immune responses and adaptive immunity by controlling TLR and cytokine signalings.In this study, we demonstrated that TLR-mediated signaling are essential for the tissue homeostasis in mice. Upon partial hepatectomy, wild-type mice show prompt liver regeneration. However, mutant mice that lack intracellular adaptor molecule essential for the activation of TLR-mediated pathways are defect in the liver regeneration after partial hepatectomy. This clearly indicates that TLR-mediated innate immunity is essential for not only host defense but also tissue homeostasis. Furthermore, we observed that IL-6 but not TNF, both of which are induced by the activation of TLR-mediated signalings, contributes to the development of acute reactive arthritis in mice. Thus, these results indicate that the TLR-mediated pathways play an important role in various biological situations, such as host defense, tissue homeostasis and incidental tissue injuries. Less