Regulation of Toll-Like Receptors in Human Monocytes and Dendritic Cells

Visintin, Alberto; Mazzoni, Alessandra; Spitzer, Jessica H.; Wyllie, David; Dower, Steven K.; Segal, David M.

doi:10.4049/jimmunol.166.1.249

Cited by 540 publications

(441 citation statements)

References 46 publications

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“…The unique TLR expression pattern, in particular the lack of TLR4 and the associated molecule MD2, suggests that the cervicovaginal epithelium is capable of responding to Gram-negative pathogens in the absence of endotoxin recognition. This is in contrast to the mechanism used by phagocytes (15,17,82), dendritic cells (83), and endothelial cells (51,84), which express TLR4 and are highly sensitive to LPS activation through the Toll/IL-1 signaling pathway.…”

Section: Discussionmentioning

confidence: 75%

Response toNeisseria gonorrhoeaeby Cervicovaginal Epithelial Cells Occurs in the Absence of Toll-Like Receptor 4-Mediated Signaling

Fichorova

Cronin

Lien

et al. 2002

The Journal of Immunology

212

174

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Toll-like receptors (TLRs) have recently been identified as fundamental components of the innate immune response to bacterial pathogens. We investigated the role of TLR signaling in immune defense of the mucosal epithelial cells of the lower female genital tract. This site provides first line defense against microbial pathogens while remaining tolerant to a complex biosystem of resident microbiota. Epithelial cells derived from normal human vagina, ectocervix, and endocervix expressed mRNA for TLR1, -2, -3, -5, and -6. However, they failed to express TLR4 as well as MD2, two essential components of the receptor complex for LPS in phagocytes and endothelial cells. Consistent with this, endocervical epithelial cells were unresponsive to protein-free preparations of lipooligosaccharide from Neisseria gonorrhoeae and LPS from Escherichia coli. However, they were capable of responding to whole Gram-negative bacteria and bacterial lysates, as demonstrated by NF-κB activation and proinflammatory cytokine production. The presence of soluble CD14, a high-affinity receptor for LPS and other bacterial ligands, enhanced the sensitivity of genital tract epithelial cells to both low and high concentrations of bacteria, suggesting that soluble CD14 can act as a coreceptor for non-TLR4 ligands. These data demonstrate that the response to N. gonorrhoeae and other Gram-negative bacteria at the mucosal surface of the female genital tract occurs in the absence of endotoxin recognition and TLR4-mediated signaling.

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Section: Discussionmentioning

confidence: 75%

Response toNeisseria gonorrhoeaeby Cervicovaginal Epithelial Cells Occurs in the Absence of Toll-Like Receptor 4-Mediated Signaling

Fichorova

Cronin

Lien

et al. 2002

The Journal of Immunology

212

174

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“…TNF-α, a largely secreted cytokine, shows strong ability to alter cell growth and differentiation activity, which potentially induce pathological changes (Beutler & Cerami, 1988). Along with cytokine release, TLR2, membrane-anchored receptors are also responsible for interacting with foreign agents and activate antigen-specific immunity (Visintin et al, 2001). Therefore, the expression levels of TNF-α and TLR2 were used to determine innate immune responses from NP-treated monocytes.…”

Section: Discussionmentioning

confidence: 99%

The responses of immune cells to iron oxide nanoparticles

Sherwood

Lackey

et al. 2016

J of Applied Toxicology

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Immune cells play an important role in recognizing and removing foreign objects, such as nanoparticles. Among various parameters, surface coatings of nanoparticles are the first contact with biological system, which critically affect nanoparticle interactions. Here, surface coating effects on nanoparticle cellular uptake, toxicity and ability to trigger immune response were evaluated on a human monocyte cell line using iron oxide nanoparticles. The cells were treated with nanoparticles of three types of coatings (negatively charged polyacrylic acid, positively charged polyethylenimine and neutral polyethylene glycol). The cells were treated at various nanoparticle concentrations (5, 10, 20, 30, 50 μg ml À1 or 2, 4, 8, 12, 20 μg cm À2 ) with 6 h incubation or treated at a nanoparticle concentration of 50 μg ml À1 (20 μg cm À2 ) at different incubation times (6, 12, 24, 48 or 72 h). Cell viability over 80% was observed for all nanoparticle treatment experiments, regardless of surface coatings, nanoparticle concentrations and incubation times. The much lower cell viability for cells treated with free ligands (e.g.~10% for polyethylenimine) suggested that the surface coatings were tightly attached to the nanoparticle surfaces. The immune responses of cells to nanoparticles were evaluated by quantifying the expression of toll-like receptor 2 and tumor necrosis factor-α. The expression of tumor necrosis factor-α and toll-like receptor 2 were not significant in any case of the surface coatings, nanoparticle concentrations and incubation times. These results provide useful information to select nanoparticle surface coatings for biological and biomedical applications.

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“…This provides more support to a model of activation whereby MR regulates the immune response in a stimulusdependent manner. TLR are expressed differentially per infected cell type or regulated differentially during the course of infection [50]. MR expression in macrophages or dendritic cells reflects the site and/or status of activation [12].…”

Section: Discussionmentioning

confidence: 99%

Synergistic regulation of Pseudomonas aeruginosa‐induced cytokine production in human monocytes by mannose receptor and TLR2

et al. 2009

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The immune response to pathogen is regulated by a combination of specific PRR, which are involved in pathogen recognition. Pseudomonas aeruginosa, a bacterium that causes life-threatening disease in immuno-compromised host, is recognized by distinct members of the TLR family. We have previously shown that viable P. aeruginosa bacteria are recognized by human monocytes mainly through TLR2. Using ligand-specific blocking antibodies, we herein show that the mannose receptor (MR), a phagocytic receptor for unopsonized P. aeruginosa bacteria, contributes equally to TLR2 in proinflammatory cytokine production by human monocytes in response to P. aeruginosa infection. Synergy of both receptors totally controls the immune response. Viable P. aeruginosa bacteria activate NF-jB and MAPK pathways and enhance TLR2-mediated signaling in MR-transfected human embryonic kidney 293 cells. Moreover, MR follows the same kinetics and colocalizes with TLR2 in the endosome during in vivo infection of human macrophages with P. aeruginosa. The studies provide the first demonstration of a significant role for MR, synergistic with TLR2, in activating a proinflammatory response to P. aeruginosa infection.Key words: Mannose receptor . NF-kB . Pseudomonas aeruginosa . TLR . TNF-a IntroductionThe innate immune system relies on a vast array of non-clonally expressed PRR to detect pathogens. PRR bind conserved molecular structures known as PAMP, which are shared by a large group of pathogens. PRR binding to microbial products elicits a signaling response within leukocytes to produce immune modulators in a PRR-dependent manner [1]. Proinflammatory cytokine production by monocyte/macrophage lineage orchestrates the immune response and predicts the outcome of infection. The overall immune response depends on the combination of engaged PRR and their specific ligands. This complexity allows the immune system not only to tailor its response to a specific pathogen but also to discriminate the site of infection or the microbial burden.Host recognition of PAMP may result in two entirely different outcomes. An appropriate response leads to the eradication of a microorganism [2], but an exaggerated inflammatory response may lead to illnesses such as sepsis and shock [3]. TLR are the best-characterized signal-generating receptors among the PRR. They initiate key inflammatory responses and shape adaptive immunity [4]. All human TLR ($11) are type I transmembrane glycoproteins containing an extracellular domain with leucinerich repeats responsible for ligand recognition and a cytoplasmic Toll/IL-1 receptor homology domain required for initiating signaling [5]. Working as homo-or heterodimers alone or with other PRR, they recognize a diverse array of microbial components in bacteria, fungi, parasites, and viruses. This includes lipid-based bacterial cell wall components such as LPS and lipopeptides, microbial protein components such as flagellin and profilin-like molecules, and nucleic acids such as dsRNA, ssRNA, and CpG DNA [6].TLR participate with additio...

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Regulation of Toll-Like Receptors in Human Monocytes and Dendritic Cells

Cited by 540 publications

References 46 publications

Response toNeisseria gonorrhoeaeby Cervicovaginal Epithelial Cells Occurs in the Absence of Toll-Like Receptor 4-Mediated Signaling

Response toNeisseria gonorrhoeaeby Cervicovaginal Epithelial Cells Occurs in the Absence of Toll-Like Receptor 4-Mediated Signaling

The responses of immune cells to iron oxide nanoparticles

Synergistic regulation of Pseudomonas aeruginosa‐induced cytokine production in human monocytes by mannose receptor and TLR2

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