Cutting Edge: Naturally Occurring Soluble Form of Mouse Toll-Like Receptor 4 Inhibits Lipopolysaccharide Signaling

Iwami, Kenichiro; Matsuguchi, Tetsuya; Matsubara, Akio; Kikuchi, Takeshi; Musikacharoen, Tipayaratn; Yoshikai, Yasunobu

doi:10.4049/jimmunol.165.12.6682

Cited by 242 publications

(196 citation statements)

References 28 publications

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“…It is likely that the interaction of sTLR2 with iPGN causes the decreased binding of iPGN to TLR2 expressed on cell surfaces, resulting in the attenuated cell signaling. The naturally occurring soluble form of mouse TLR4 that is expressed by alternatively spliced mouse TLR4 mRNA has been shown to attenuate but not completely inhibit LPS-elicited NF-B activities to the level of 50 -60% of those observed for controls (38). These results indicate that the extracellular TLR domain alone does not explain all the activity of TLR-ligand interaction.…”

Section: Discussionmentioning

confidence: 46%

The Extracellular Toll-like Receptor 2 Domain Directly Binds Peptidoglycan Derived from Staphylococcus aureus

Iwaki

Mitsuzawa

Murakami

et al. 2002

Journal of Biological Chemistry

162

130

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Toll-like receptor 2 (TLR2) has been recognized to mediate cell signaling in response to peptidoglycan (PGN), a major cell wall component of Gram-positive bacteria. The mechanism by which TLR2 recognizes PGN is unknown. It is not even clear whether TLR2 directly binds to PGN. In this study, we generated a soluble form of recombinant TLR2 (sTLR2) possessing only its putative extracellular domain by using the baculovirus expression system to examine the direct interaction between sTLR2 and PGN. sTLR2 bound avidly to insoluble PGN (iPGN) from Staphylococcus aureus coated onto microtiter wells in a concentration-dependent manner. In contrast, sTLR2 exhibited a very weak binding to lipopolysaccharide. iPGN cosedimented sTLR2 after the mixture of iPGN and sTLR2 had been incubated and centrifuged. sTLR2 partially attenuated the iPGN-induced NF-B activation in TLR2-transfected HEK 293 cells and the iPGN-induced IL-8 secretion in U937 cells. One of anti-human TLR2 monoclonal antibodies, which blocked iPGN-induced NF-B activation in TLR2-transfected cells, inhibited the binding of sTLR2 to iPGN. In addition, we found that sCD14 interacted with sTLR2 and increased the binding of sTLR2 to iPGN. From these results, we conclude that the extracellular TLR2 domain directly binds to PGN.

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Section: Discussionmentioning

confidence: 46%

The Extracellular Toll-like Receptor 2 Domain Directly Binds Peptidoglycan Derived from Staphylococcus aureus

Iwaki

Mitsuzawa

Murakami

et al. 2002

Journal of Biological Chemistry

162

130

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“…Therefore, TLR-mediated signaling events contain negative feedback mechanisms. For example, soluble decoy TLRs (sTLR-2/-4) antagonize ligand binding and potently attenuate TLR-induced effector functions (38,39). Different intracellular negative regulators have been uncovered such as MyD88s, IRAKM, TOLLIP, A20, SOCS1, PI3K, and NOD2 (40 -42).…”

Section: Discussionmentioning

confidence: 99%

Sporozoite-Mediated Hepatocyte Wounding Limits Plasmodium Parasite Development via MyD88-Mediated NF-κB Activation and Inducible NO Synthase Expression

Torgler

Bongfen

Romero

et al. 2008

The Journal of Immunology

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Plasmodium sporozoites traverse several host cells before infecting hepatocytes. In the process, the plasma membranes of the cells are ruptured, resulting in the release of cytosolic factors into the microenvironment. This released endogenous material is highly stimulatory/immunogenic and can serve as a danger signal initiating distinct responses in various cells. Thus, our study aimed at characterizing the effect of cell material leakage during Plasmodium infection on cultured mouse primary hepatocytes and HepG2 cells. We observed that wounded cell-derived cytosolic factors activate NF-κB, a main regulator of host inflammatory responses, in cells bordering wounded cells, which are potential host cells for final parasite infection. This activation of NF-κB occurred shortly after infection and led to a reduction of infection load in a time-dependent manner in vitro and in vivo, an effect that could be reverted by addition of the specific NF-κB inhibitor BAY11-7082. Furthermore, no NF-κB activation was observed when Spect−/− parasites, which are devoid of hepatocyte traversing properties, were used. We provide further evidence that NF-κB activation causes the induction of inducible NO synthase expression in hepatocytes, and this is, in turn, responsible for a decrease in Plasmodium-infected hepatocytes. Furthermore, primary hepatocytes from MyD88−/− mice showed no NF-κB activation and inducible NO synthase expression upon infection, suggesting a role of the Toll/IL-1 receptor family members in sensing cytosolic factors. Indeed, lack of MyD88 significantly increased infection in vitro and in vivo. Thus, host cell wounding due to parasite migration induces inflammation which limits the extent of parasite infection.

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“…It is assumed that specific insertions in LRR of each TLR provide specific ligand binding sites (23) But not only pathogens try to repress TLR activation, also a variety of endogenous mechanisms exist to contain the pro-inflammatory TLR cascade. A soluble form of TLR2 was found to be expressed in humans and soluble TLR4 was measured in mice (30,31). These soluble forms might function as decoy receptors, blocking TLR responses by binding to coreceptors or ligands.…”

Section: Toll-like Receptors At a Glancementioning

confidence: 99%

TLRs and chronic inflammation

Ospelt

Gay

2010

The International Journal of Biochemistry & Cell Biology

162

127

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After the discovery of Toll-like receptors (TLRs), innate immune mechanisms came back in the focus of scientific research. With more and more mechanisms of TLR biology known, it has become clear that these and also other innate immune receptors are not only of crucial importance in the immune response to invading pathogens, but also play a role in the homeostasis of commensal flora and in the response to stress and danger signals. In this respect, increasing evidence is found that inappropriate quantity or quality of TLR ligands or aberrant response to TLR activation plays a role in a variety of chronic inflammatory diseases. In this review, an overview of the currently known TLRs and their signaling pathways is given and reports about their expression and activation in chronic inflammatory diseases are recapitulated. TLRs and chronic inflammation Abstract:After the discovery of Toll-like receptors (TLRs), innate immune mechanisms came back in the focus of scientific research. With more and more mechanisms of TLR biology known, it has become clear that these and also other innate immune receptors are not only of crucial importance in the immune response to invading pathogens, but also play a role in the homeostasis of commensal flora and in the response to stress and danger signals. In this respect, increasing evidence is found that inappropriate quantity or quality of TLR ligands or aberrant response to TLR activation plays a role in a variety of chronic inflammatory diseases.In this review, an overview of the currently known TLRs and their signaling pathways isgiven and reports about their expression and activation in chronic inflammatory diseases are recapitulated.2

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Cutting Edge: Naturally Occurring Soluble Form of Mouse Toll-Like Receptor 4 Inhibits Lipopolysaccharide Signaling

Cited by 242 publications

References 28 publications

The Extracellular Toll-like Receptor 2 Domain Directly Binds Peptidoglycan Derived from Staphylococcus aureus

The Extracellular Toll-like Receptor 2 Domain Directly Binds Peptidoglycan Derived from Staphylococcus aureus

Sporozoite-Mediated Hepatocyte Wounding Limits Plasmodium Parasite Development via MyD88-Mediated NF-κB Activation and Inducible NO Synthase Expression

TLRs and chronic inflammation

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