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Haruhiko Takada

Bio: Haruhiko Takada is an academic researcher from Tohoku University. The author has contributed to research in topics: Lipopolysaccharide & Proinflammatory cytokine. The author has an hindex of 47, co-authored 148 publications receiving 10455 citations. Previous affiliations of Haruhiko Takada include Aichi Medical University & Matsumoto Dental University.


Papers
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Journal ArticleDOI
01 Oct 1999-Immunity
TL;DR: It is demonstrated that TLR2 and TLR4 recognize different bacterial cell wall components in vivo andTLR2 plays a major role in Gram-positive bacterial recognition.

3,364 citations

Journal ArticleDOI
TL;DR: It is reported that in drosophila, recognition of diaminopimelic acid–type peptidoglycan by the pattern-recognition receptor PGRP-LE was crucial for the induction of autophagy and that Autophagy prevented the intracellular growth of Listeria monocytogenes and promoted host survival after this infection.
Abstract: Autophagy, an evolutionally conserved homeostatic process for catabolizing cytoplasmic components, has been linked to the elimination of intracellular pathogens during mammalian innate immune responses. However, the mechanisms underlying cytoplasmic infection-induced autophagy and the function of autophagy in host survival after infection with intracellular pathogens remain unknown. Here we report that in drosophila, recognition of diaminopimelic acid-type peptidoglycan by the pattern-recognition receptor PGRP-LE was crucial for the induction of autophagy and that autophagy prevented the intracellular growth of Listeria monocytogenes and promoted host survival after this infection. Autophagy induction occurred independently of the Toll and IMD innate signaling pathways. Our findings define a pathway leading from the intracellular pattern-recognition receptors to the induction of autophagy to host defense.

367 citations

Journal ArticleDOI
TL;DR: It is suggested that Nod1 and Nod2 agonists in combination with TLR3, TLR4, and TLR9 agonists synergistically induce IL-12 and IFN-γ production in DCs to induce Th1-lineage immune responses.
Abstract: A synthetic Nod2 agonist, muramyldipeptide (MDP), and two Nod1 agonists, FK565 and FK156, mimic the bacterial peptidoglycan moiety and are powerful adjuvants that induce cell-mediated immunity, especially delayed-type hypersensitivity. In this study, we used human dendritic cell (DC) cultures to examine possible T helper type 1 (Th1) responses induced by MDP and FK565/156 in combination with various synthetic Toll-like receptor (TLR) agonists, including synthetic lipid A (TLR4 agonist), the synthetic triacyl lipopeptide Pam3CSSNA (TLR2 agonist), poly(I:C) (TLR3 agonist), and CpG DNA (TLR9 agonist). Immature DCs derived from human monocytes expressed mRNAs for Nod1, Nod2, TLR2, TLR3, TLR4, and TLR9. The stimulation of DCs with MDP and FK565 in combination with lipid A, poly(I:C), and CpG DNA, but not with Pam3CSSNA, synergistically induced interleukin-12 (IL-12) p70 and gamma interferon (IFN-γ), but not IL-18, in culture supernatants and induced IL-15 on the cell surface. In correlation with the cytokine induction, an upregulation of the mRNA expression of these cytokine genes was observed. Notably, IL-12 p35 mRNA expression increased >1,000-fold upon stimulation with lipid A plus either MDP or FK565 compared with stimulation with each stimulant alone. In contrast, for the expression of CD83 and costimulatory molecules such as CD40, CD80, and CD86, no synergistic effects were observed upon stimulation with Nod plus TLR agonists. The culture supernatants of DCs stimulated with lipid A plus either MDP or FK565 activated human T cells to produce high levels of IFN-γ, and the activity was attributable to DC-derived IL-12. These findings suggest that Nod1 and Nod2 agonists in combination with TLR3, TLR4, and TLR9 agonists synergistically induce IL-12 and IFN-γ production in DCs to induce Th1-lineage immune responses.

364 citations

Journal ArticleDOI
TL;DR: It is reported that, in larvae, the imd-mediated antibacterial defense is activated by peptidoglycan-recognition protein (PGRP)-LE, a PGRP-family member in Drosophila, which acts as a pattern- Recognition receptor to the diaminopimelic acid-type peptIDoglycan and activates both the proteolytic cascade and intracellular signaling in Dosophila immunity.
Abstract: In Drosophila, microbial infection activates an antimicrobial defense system involving the activation of proteolytic cascades in the hemolymph and intracellular signaling pathways, the immune deficiency (imd) and Toll pathways, in immune-responsive tissues. The mechanisms for microbial recognition are largely unknown. We report that, in larvae, the imd-mediated antibacterial defense is activated by peptidoglycan-recognition protein (PGRP)-LE, a PGRP-family member in Drosophila. Consistent with this, PGRP-LE binds to the diaminopimelic acid-type peptidoglycan, a cell-wall component of the bacteria capable of activating the imd pathway, but not to the lysine-type peptidoglycan. Moreover, PGRP-LE activates the prophenoloxidase cascade, a proteolytic cascade in the hemolymph. Therefore, PGRP-LE acts as a pattern-recognition receptor to the diaminopimelic acid-type peptidoglycan and activates both the proteolytic cascade and intracellular signaling in Drosophila immunity.

328 citations

Journal ArticleDOI
TL;DR: Findings indicate that TLR and NOD in various epithelial cells are functional receptors that induce anti-bacterial responses in general without being accompanied by inflammatory responses.

312 citations


Cited by
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Journal ArticleDOI
TL;DR: Microbial recognition by Toll-like receptors helps to direct adaptive immune responses to antigens derived from microbial pathogens to distinguish infectious nonself from noninfectious self.
Abstract: ▪ Abstract The innate immune system is a universal and ancient form of host defense against infection. Innate immune recognition relies on a limited number of germline-encoded receptors. These receptors evolved to recognize conserved products of microbial metabolism produced by microbial pathogens, but not by the host. Recognition of these molecular structures allows the immune system to distinguish infectious nonself from noninfectious self. Toll-like receptors play a major role in pathogen recognition and initiation of inflammatory and immune responses. Stimulation of Toll-like receptors by microbial products leads to the activation of signaling pathways that result in the induction of antimicrobial genes and inflammatory cytokines. In addition, stimulation of Toll-like receptors triggers dendritic cell maturation and results in the induction of costimulatory molecules and increased antigen-presenting capacity. Thus, microbial recognition by Toll-like receptors helps to direct adaptive immune responses ...

8,041 citations

Journal ArticleDOI
TL;DR: Rapid progress that has recently improved the understanding of the molecular mechanisms that mediate TLR signalling is reviewed.
Abstract: One of the mechanisms by which the innate immune system senses the invasion of pathogenic microorganisms is through the Toll-like receptors (TLRs), which recognize specific molecular patterns that are present in microbial components. Stimulation of different TLRs induces distinct patterns of gene expression, which not only leads to the activation of innate immunity but also instructs the development of antigen-specific acquired immunity. Here, we review the rapid progress that has recently improved our understanding of the molecular mechanisms that mediate TLR signalling.

7,906 citations

Journal ArticleDOI
07 Dec 2000-Nature
TL;DR: It is shown that cellular response to CpG DNA is mediated by a Toll-like receptor, TLR9, and vertebrate immune systems appear to have evolved a specific Toll- like receptor that distinguishes bacterial DNA from self-DNA.
Abstract: DNA from bacteria has stimulatory effects on mammalian immune cells, which depend on the presence of unmethylated CpG dinucleotides in the bacterial DNA. In contrast, mammalian DNA has a low frequency of CpG dinucleotides, and these are mostly methylated; therefore, mammalian DNA does not have immuno-stimulatory activity. CpG DNA induces a strong T-helper-1-like inflammatory response. Accumulating evidence has revealed the therapeutic potential of CpG DNA as adjuvants for vaccination strategies for cancer, allergy and infectious diseases. Despite its promising clinical use, the molecular mechanism by which CpG DNA activates immune cells remains unclear. Here we show that cellular response to CpG DNA is mediated by a Toll-like receptor, TLR9. TLR9-deficient (TLR9-/-) mice did not show any response to CpG DNA, including proliferation of splenocytes, inflammatory cytokine production from macrophages and maturation of dendritic cells. TLR9-/- mice showed resistance to the lethal effect of CpG DNA without any elevation of serum pro-inflammatory cytokine levels. The in vivo CpG-DNA-mediated T-helper type-1 response was also abolished in TLR9-/- mice. Thus, vertebrate immune systems appear to have evolved a specific Toll-like receptor that distinguishes bacterial DNA from self-DNA.

6,188 citations

Journal ArticleDOI
18 Oct 2001-Nature
TL;DR: It is shown that mammalian TLR3 recognizes dsRNA, and that activation of the receptor induces the activation of NF-κB and the production of type I interferons (IFNs).
Abstract: Toll-like receptors (TLRs) are a family of innate immune-recognition receptors that recognize molecular patterns associated with microbial pathogens, and induce antimicrobial immune responses. Double-stranded RNA (dsRNA) is a molecular pattern associated with viral infection, because it is produced by most viruses at some point during their replication. Here we show that mammalian TLR3 recognizes dsRNA, and that activation of the receptor induces the activation of NF-kappaB and the production of type I interferons (IFNs). TLR3-deficient (TLR3-/-) mice showed reduced responses to polyinosine-polycytidylic acid (poly(I:C)), resistance to the lethal effect of poly(I:C) when sensitized with d-galactosamine (d-GalN), and reduced production of inflammatory cytokines. MyD88 is an adaptor protein that is shared by all the known TLRs. When activated by poly(I:C), TLR3 induces cytokine production through a signalling pathway dependent on MyD88. Moreover, poly(I:C) can induce activation of NF-kappaB and mitogen-activated protein (MAP) kinases independently of MyD88, and cause dendritic cells to mature.

6,066 citations

Journal ArticleDOI
TL;DR: This unit discusses mammalian Toll receptors (TLR1‐10) that have an essential role in the innate immune recognition of microorganisms and are discussed are TLR‐mediated signaling pathways and antibodies that are available to detect specific TLRs.
Abstract: The innate immune system in drosophila and mammals senses the invasion of microorganisms using the family of Toll receptors, stimulation of which initiates a range of host defense mechanisms. In drosophila antimicrobial responses rely on two signaling pathways: the Toll pathway and the IMD pathway. In mammals there are at least 10 members of the Toll-like receptor (TLR) family that recognize specific components conserved among microorganisms. Activation of the TLRs leads not only to the induction of inflammatory responses but also to the development of antigen-specific adaptive immunity. The TLR-induced inflammatory response is dependent on a common signaling pathway that is mediated by the adaptor molecule MyD88. However, there is evidence for additional pathways that mediate TLR ligand-specific biological responses.

5,915 citations