Mechanism regulating cell surface expression and activation of Toll‐like receptor 4

Saitoh, Shin-Ichiroh; Miyake, Kensuke

doi:10.1002/tcr.20093

Cited by 21 publications

(15 citation statements)

References 62 publications

(66 reference statements)

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“…Therefore, it is conceivable that the observed difference in the activation of the downstream signaling cascade and the overall difference in the profile of cytokine production may result from the different interaction between TLR4 and LPS or PLY. LPS directly binds to MD2 associated with the extracellular domain of TLR4 and then induces clustering of TLR4/MD2, which leads to the activation of two main signaling pathways downstream of TLR4, namely, the MyD88/Toll-IL-1 receptor (TIR) domain-containing adaptor protein (TIRAP)-dependent pathway and the TIR domain-containing adaptor inducing beta interferon (IFN-␤) (TRIF)/TRIF-related adaptor molecule (TRAM)-dependent pathway (46). The MyD88/TIRAPdependent pathway is involved preferentially in the induction of proinflammatory cytokines, whereas the TRIF/TRAM-dependent pathway is involved in the induction of IFN-␤ rather than proinflammatory cytokines (3).…”

Section: Discussionmentioning

confidence: 99%

Critical Involvement of Pneumolysin in Production of Interleukin-1α and Caspase-1-Dependent Cytokines in Infection withStreptococcus pneumoniaeIn Vitro: a Novel Function of Pneumolysin in Caspase-1 Activation

et al. 2008

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Pneumolysin is a pore-forming cytolysin known as a major virulence determinant of Streptococcus pneumoniae. This protein toxin has also been shown to activate the Toll-like receptor 4 (TLR4) signaling pathway. In this study, a mutant S. pneumoniae strain deficient in pneumolysin (⌬ply) and a recombinant pneumolysin protein (rPLY) were constructed. Upon infection of macrophages in vitro, the ability to induce the production of interleukin-1␣ (IL-1␣), IL-1␤, and IL-18 was severely impaired in the ⌬ply mutant, whereas there was no marked difference in the induction of tumor necrosis factor alpha (TNF-␣) and IL-12p40 between the wild type and the ⌬ply mutant of S. pneumoniae. When macrophages were stimulated with rPLY, the production of IL-1␣, IL-1␤, and IL-18 was strongly induced in a TLR4-dependent manner, whereas lipopolysaccharide, a canonical TLR4 agonist, hardly induced these cytokines. In contrast, lipopolysaccharide was more potent than rPLY in inducing the production of TNF-␣, IL-6, and IL-12p40, the cytokines requiring no caspase activation. Activation of caspase-1 was observed in macrophages stimulated with rPLY but not in those stimulated with lipopolysaccharide, and the level of activation was higher in macrophages infected with wild-type S. pneumoniae than in those infected with the ⌬ply mutant. These results clearly indicate that pneumolysin plays a key role in the host response to S. pneumoniae, particularly in the induction of caspase-1-dependent cytokines.

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Section: Discussionmentioning

confidence: 99%

Critical Involvement of Pneumolysin in Production of Interleukin-1α and Caspase-1-Dependent Cytokines in Infection withStreptococcus pneumoniaeIn Vitro: a Novel Function of Pneumolysin in Caspase-1 Activation

et al. 2008

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“…The molecular mechanisms by which TLR4 stays in the Golgi/ER and migrates to the cell surface are currently unknown. MD-2 has been shown not only to be essential for TLR4 binding with LPS but also indispensable for cell surface expression of TLR4 in many cell types, including HEK293 cells, bone marrow-derived dendritic cells, embryonic fibroblasts, and macrophages (17)(18)(19). Physical interaction between TLR4 and MD-2 was shown to be essential for the maturation of TLR4 and its presence in the cell membrane (17).…”

mentioning

confidence: 99%

“…A protein associated with TLR4 (PRAT4A) was also reported to play a role in the process of TLR4 maturation/glycosylation in bone marrow-derived macrophages (20,21). PRAT4A likely a component of the machinery facilitating TLR4/MD-2 trafficking to the cell surface (19,22). Trafficking of TLR4 to the membrane of macrophages in response to LPS is also shown to be reactive oxygen species-dependent (23), and heme oxygenase-1/CO suppresses TLR4 signaling by regulating the interaction of TLR4 with caveolin-1 (24).…”

mentioning

confidence: 99%

Carbon Monoxide Suppresses Membrane Expression of TLR4 via Myeloid Differentiation Factor-2 in βTC3 Cells

Rocuts

Zhang

et al. 2010

The Journal of Immunology

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Islet allografts from donor mice exposed to CO are protected from immune rejection after transplantation via the suppression of membrane trafficking/activation of TLR4 in islets/β cells. The molecular mechanisms of how CO suppresses TLR4 activation in β cells remain unclear and are the focus of this study. Cells of the insulinoma cell line, βTC3, were stably transfected with pcDNA3-TLR4-YFP and pDsRed-Monomer-Golgi plasmids and used to identify the subcellular distribution of TLR4 before and after LPS stimulation by confocal microscopy. Immunofluorescence analysis revealed that TLR4 mainly resides in the Golgi apparatus in βTC3 cells when in a quiescent state. LPS stimulation led to a rapid trafficking of TLR4 from the Golgi to the cell membrane. Physical interaction between TLR4 and myeloid differentiation factor-2 (MD-2) was confirmed by immunoprecipitation. Depleting MD-2 using small interfering RNA or blocking the N-glycosylation of cells using tunicamycin blocked membrane trafficking of TLR4. Pre-exposing cells to CO at a concentration of 250 parts per million suppressed membrane trafficking of TLR4 via inhibiting its glycosylation and the interaction between TLR4 and MD-2. In conclusion, MD-2 is required for the glycosylation of TLR4 and its consequent membrane trafficking in βTC3 cells. CO suppresses membrane activation of TLR4 via blocking its glycosylation and the physical interaction between TLR4 and MD-2.

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“…LPS forms a complex with LPS-binding protein in serum leading to the conversion of oligomeric micelles of LPS to monomers, which are delivered to CD14. Monomeric LPS is known to bind TLR4/MD-2/CD14 complex (4). Lipid A, which possesses most of the biological activities of LPS, is acylated with hydroxy saturated fatty acids.…”

mentioning

confidence: 99%

Fatty Acids Modulate Toll-like Receptor 4 Activation through Regulation of Receptor Dimerization and Recruitment into Lipid Rafts in a Reactive Oxygen Species-dependent Manner

Wong

Kwon

Choi

et al. 2009

Journal of Biological Chemistry

483

382

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The saturated fatty acids acylated on Lipid A of lipopolysaccharide (LPS) or bacterial lipoproteins play critical roles in ligand recognition and receptor activation for Toll-like Receptor 4 (TLR4) and TLR2. The results from our previous studies demonstrated that saturated and polyunsaturated fatty acids reciprocally modulate the activation of TLR4. However, the underlying mechanism has not been understood. Here, we report for the first time that the saturated fatty acid lauric acid induced dimerization and recruitment of TLR4 into lipid rafts, however, dimerization was not observed in non-lipid raft fractions. Similarly, LPS and lauric acid enhanced the association of TLR4 with MD-2 and downstream adaptor molecules, TRIF and MyD88, into lipid rafts leading to the activation of downstream signaling pathways and target gene expression. However, docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, inhibited LPS-or lauric acid-induced dimerization and recruitment of TLR4 into lipid raft fractions. Together, these results demonstrate that lauric acid and DHA reciprocally modulate TLR4 activation by regulation of the dimerization and recruitment of TLR4 into lipid rafts. In addition, we showed that TLR4 recruitment to lipid rafts and dimerization were coupled events mediated at least in part by NADPH oxidase-dependent reactive oxygen species generation. These results provide a new insight in understanding the mechanism by which fatty acids differentially modulate TLR4-mediated signaling pathway and consequent inflammatory responses which are implicated in the development and progression of many chronic diseases.

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Mechanism regulating cell surface expression and activation of Toll‐like receptor 4

Cited by 21 publications

References 62 publications

Critical Involvement of Pneumolysin in Production of Interleukin-1α and Caspase-1-Dependent Cytokines in Infection withStreptococcus pneumoniaeIn Vitro: a Novel Function of Pneumolysin in Caspase-1 Activation

Critical Involvement of Pneumolysin in Production of Interleukin-1α and Caspase-1-Dependent Cytokines in Infection withStreptococcus pneumoniaeIn Vitro: a Novel Function of Pneumolysin in Caspase-1 Activation

Carbon Monoxide Suppresses Membrane Expression of TLR4 via Myeloid Differentiation Factor-2 in βTC3 Cells

Fatty Acids Modulate Toll-like Receptor 4 Activation through Regulation of Receptor Dimerization and Recruitment into Lipid Rafts in a Reactive Oxygen Species-dependent Manner

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