▪ 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 ...

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Innate Immune Recognition

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.

Toll-like receptor signalling

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.

A Toll-like receptor recognizes bacterial DNA.

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.

Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3.

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.

Toll-like receptors.

Oral Spirochetal Species Detection Using a Polymerase Chain Reaction

PURPOSE:To obtain an analgesic and anti-inflammatory agent having antitumor action and remedying effect for infectious diseases and useful for the treatment of headache, toothache, neuralgia, post-operation pain, etc., by using a muramyl dipeptide derivative as an active component. CONSTITUTION:The objective agent can be produced by using a compound of formula I [R1 is H or lower - medium acyl; R2 is H or lower alkyl; R3 is OH or group of formula II (m is 1-30); R4 is lower acyl, etc.] or its salt as an active component and converting the component to a drug with a proper carrier, excipient, etc., by conventional process. Dose: 0.05-10mg daily for adult. The compound of formula I is e.g. N -(N-acetylmuramyl-N-methyl-L- alanyl-D-isoglutaminyl)--N -stearoyl-L-lysine.

Analgesic and anti-inflammatory agent containing muramyl dipeptide derivative

Synthesis of lipid A 1 isolated from Helicobacter pylori strain 206-1 has been achieved in 2.2% total yield through 14 steps from d -glucosamine by employing a p-(trifluoromethyl)benzyl group for protection of the hydroxy group on the 3-hydroxy fatty acid residue. The synthetic specimen was identical with the natural counterpart in chromatographic, spectroscopic, and biological aspects. A structural analogue 2 which lacks the ethanolamine residue of 1 was also synthesized, and 2 was found to exhibit less potent IL-1β-inducing activity than 1.

Synthesis of Helicobacter pylori Lipid A and Its Analogue Using p-(Trifluoromethyl)benzyl Protecting Group.

PROBLEM TO BE SOLVED: To provide an ameliorating or improving agent for oral function which can be easily applied to oral mucosa, has a good adhesion and permeability to oral mucosa, hardly causes choke, accidental ingestion and aspiration and the like, is excellent in amelioration or improvement of oral function and is suitable for oral rehabilitation.SOLUTION: There is provided an ameliorating or improving agent for oral function in which an essential oil of Cymbopogon plants is contained in a shea butter.

Ameliorating or improving agent for oral function, and drugs, quasi drugs, cosmetics or foods and drinks containing thereof

whichpossessesfour tetradecanoyl groupsatthe2-and2'-amino, and3-and3'-hydroxyl groups(LA-17-PP), andeachtwoofthe (R)-3-hydroxytetradecanoyl andtetradecanoyl groupsatthe2-and2'-amino and3-and3'-hydroxyl groups, respectively (LA-18-PP), werefarless endotoxic thansynthetic (506, LA-15-PP) andbacterial Escherichia coli typelipid A's;neither compoundshowed any detectable lethal toxicity inchicken embryos or preparatory activity forthelocal Shwartzman reaction inrabbits. Alsobothcompounds were onlyweakly pyrogenic and comparably less lethally toxic ingalactosamine-loaded micethanthereference synthetic andbacterial lipid A's andasynthetic counterpart tobiosynthetic lipid A precursorIa(406, LA-14-PP). Nevertheless, LA-17-PP and LA-18-PP exhibited definite invivo immunoadjuvant activity inmice, andtheability toinduce apossible tumor necrosis factor andalpha/beta interferon inMycobacterium bovis BCG andPropionibacterium acnes-primed mice,respectively, although theseactivities were weakerthanthoseofthereference lipid A's.4'Monophosphate analogs oftheabove twotestcompounds exhibited neither endotoxic norbeneficial activities, buttheyshowedremarkable invitro bioactivities comparable tothose ofthecorresponding bisphosphate compounds; theability toactivate thehumancomplement system andtheclotting enzymecascade ofhorseshoe crabamoebocyte lysate, stimulatory effects on guinea pigandmurineperitoneal macrophages, andmurine splenocytes.

Tomohiko Ogawa

Papers

Oral Spirochetal Species Detection Using a Polymerase Chain Reaction

Analgesic and anti-inflammatory agent containing muramyl dipeptide derivative

Synthesis of Helicobacter pylori Lipid A and Its Analogue Using p-(Trifluoromethyl)benzyl Protecting Group.

Ameliorating or improving agent for oral function, and drugs, quasi drugs, cosmetics or foods and drinks containing thereof

Immunobiological Activities ofSynthetic LipidA Analogswith LowEndotoxicity