Toll-Like Receptor (TLR)2 and TLR4 Agonists Regulate CCR Expression in Human Monocytic Cells

Parker, Lisa C.; Whyte, Moira K. B.; Vogel, Stefanie N.; Dower, Steven K.; Sabroe, Ian

doi:10.4049/jimmunol.172.8.4977

Cited by 90 publications

(75 citation statements)

References 46 publications

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“…CCR2 and CD14 were down-regulated by LPS. This pattern is similar to that seen in purified peripheral blood monocytes and macrophages (21)(22)(23). FIGURE 1.…”

Section: Lps Induces Large-scale Changes In Gene Expression In Whole supporting

confidence: 62%

Identification of High and Low Responders to Lipopolysaccharide in Normal Subjects: An Unbiased Approach to Identify Modulators of Innate Immunity

Wurfel

Park

Radella

et al. 2005

The Journal of Immunology

110

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LPS stimulates a vigorous inflammatory response from circulating leukocytes that varies greatly from individual to individual. The goal of this study was to use an unbiased approach to identify differences in gene expression that may account for the high degree of interindividual variability in inflammatory responses to LPS in the normal human population. We measured LPS-induced cytokine production ex vivo in whole blood from 102 healthy human subjects and identified individuals who consistently showed either very high or very low responses to LPS (denoted lpshigh and lpslow, respectively). Comparison of gene expression profiles between the lpshigh and lpslow individuals revealed 80 genes that were differentially expressed in the presence of LPS and 21 genes that were differentially expressed in the absence of LPS (p < 0.005, ANOVA). Expression of a subset of these genes was confirmed using real-time RT-PCR. Functional relevance for one gene confirmed to be expressed at a higher level in lpshigh, adipophilin, was inferred when reduction in adipophilin mRNA by small interfering RNA in the human monocyte-like cell line THP-1 resulted in a modest but significant reduction in LPS-induced MCP-1 mRNA expression. These data illustrate a novel approach to the identification of factors that determine interindividual variability in innate immune inflammatory responses and identify adipophilin as a novel potential regulator of LPS-induced MCP-1 production in human monocytes.

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“…CCR2 and CD14 were down-regulated by LPS. This pattern is similar to that seen in purified peripheral blood monocytes and macrophages (21)(22)(23). FIGURE 1.…”

Section: Lps Induces Large-scale Changes In Gene Expression In Whole supporting

confidence: 62%

Identification of High and Low Responders to Lipopolysaccharide in Normal Subjects: An Unbiased Approach to Identify Modulators of Innate Immunity

Wurfel

Park

Radella

et al. 2005

The Journal of Immunology

110

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“…As lipoproteins and their Pam 3 C motif are known ligands of TLR2 (2,5,11,12,17), we further analyzed the role of this cellular lipopeptide detector for secretion of CXCL13. Using a neutralizing TLR2 antibody (15), we could substantially reduce the CXCL13 release upon exposure of monocytes to B. garinii.…”

Section: Discussionmentioning

confidence: 99%

Borrelia gariniiInduces CXCL13 Production in Human Monocytes through Toll-Like Receptor 2

Rupprecht¹,

Kirschning

Popp³

et al. 2007

Infect Immun

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Recent studies have suggested an important role for the B-cell-attracting chemokine CXCL13 in the B-cell-dominated cerebrospinal fluid (CSF) infiltrate in patients with neuroborreliosis (NB). High levels of CXCL13 were present in the CSF of NB patients. It has not been clear, however, whether high CSF CXCL13 titers are specific for NB or are a characteristic of other spirochetal diseases as well. Furthermore, the mechanisms leading to the observed CXCL13 expression have not been identified yet. Here we describe similarly elevated CSF CXCL13 levels in patients with neurosyphilis, while pneumococcal meningitis patient CSF do not have high CXCL13 levels. In parallel, challenge of human monocytes in vitro with two of the spirochetal causative organisms, Borrelia garinii (the Borrelia species most frequently found in NB patients) and Treponema pallidum, but not challenge with pneumococci, induced CXCL13 release. This finding implies that a common spirochetal motif is a CXCL13 inducer. Accordingly, we found that the lipid moiety N-palmitoyl-S-(bis[palmitoyloxy]propyl)cystein (Pam 3 C) (three palmitoyl residues bound to N-terminal cysteine) of the spirochetal lipoproteins is critical for the CXCL13 induction in monocytes. As the Pam 3 C motif is known to signal via Toll-like receptor 2 (TLR2) and an anti-TLR2 monoclonal antibody blocked CXCL13 production of human monocytes incubated with B. garinii, this suggests that TLR2 is a major mediator of Borrelia-induced secretion of CXCL13 from human monocytes.Spirochetes are a group of bacteria that can be distinguished morphologically from other bacteria based on the fact that they are thin, long, and helical or corkscrew shaped. While in the northern hemisphere Borrelia burgdorferi is the predominant spirochete responsible for neuroinfectious diseases, infections of the central nervous system (CNS) with Treponema pallidum are endemic in regions all over the world. Moreover, a dramatic increase in the incidence of syphilis has been noted in several countries (9). In contrast to their high prevalence, the pathogenesis of neuroborreliosis (NB) and neurosyphilis (NS) is not yet well understood. After crossing the blood-brain barrier, both spirochetes elicit an inflammatory response in the cerebrospinal fluid (CSF), predominantly mediated by mononuclear cells. This contrasts with the massive invasion of polymorphonuclear cells into the CSF of patients with pneumococcal meningitis (PM), the most frequent bacterial infection of the adult CNS.It is assumed that the infiltration and the composition of the immunocompetent cells in the CSF are mainly the result of the intrathecal production of chemokines. Besides being grouped according to common motifs in their amino acid sequences, chemokines can be subdivided according to the cell populations that they predominantly attract. B lymphocytes, in contrast to other leukocytes, show substantial migration in response to only a very few chemokines, namely, CCL19, CCL21, CXCL12, and CXCL13 (3). Since the proportion of B lymphocytes in the C...

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“…Cell lysates were prepared from approximately 500,000 BEAS-2B cells, and Western blot analysis was conducted as previously described (45). Samples were probed with anti-MyD88 (1:500; Cell Signaling Technology, Danvers, MA) or anti-actin (1:10,000; Sigma-Aldrich), all detected using a horseradish peroxidase (HRP)-coupled anti-rabbit secondary Ab (1:2,000; Cell Signaling Technology) and Amersham ECL Western blotting detection reagents (Amersham Pharmacia Biotech, Buckinghamshire, United Kingdom).…”

Section: Methodsmentioning

confidence: 99%

Role of Interleukin-1 and MyD88-Dependent Signaling in Rhinovirus Infection

Stokes

Ismail

Dick

et al. 2011

J Virol

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Rhinoviral infection is an important trigger of acute inflammatory exacerbations in patients with underlying airway disease. We have previously established that interleukin-1␤ (IL-1␤) is central in the communication between epithelial cells and monocytes during the initiation of inflammation. In this study we explored the roles of IL-1␤ and its signaling pathways in the responses of airway cells to rhinovirus-1B (RV-1B) and further determined how responses to RV-1B were modified in a model of bacterial coinfection. Our results revealed that IL-1␤ dramatically potentiated RV-1B-induced proinflammatory responses, and while monocytes did not directly amplify responses to RV-1B alone, they played an important role in the responses observed with our coinfection model. MyD88 is the essential signaling adapter for IL-1␤ and most Toll-like receptors. To examine the role of MyD88 in more detail, we created stable MyD88 knockdown epithelial cells using short hairpin RNA (shRNA) targeted to MyD88. We determined that IL-1␤/MyD88 plays a role in regulating RV-1B replication and the inflammatory response to viral infection of airway cells. These results identify central roles for IL-1␤ and its signaling pathways in the production of CXCL8, a potent neutrophil chemoattractant, in viral infection. Thus, IL-1␤ is a viable target for controlling the neutrophilia that is often found in inflammatory airway disease and is exacerbated by viral infection of the airways.

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Toll-Like Receptor (TLR)2 and TLR4 Agonists Regulate CCR Expression in Human Monocytic Cells

Cited by 90 publications

References 46 publications

Identification of High and Low Responders to Lipopolysaccharide in Normal Subjects: An Unbiased Approach to Identify Modulators of Innate Immunity

Identification of High and Low Responders to Lipopolysaccharide in Normal Subjects: An Unbiased Approach to Identify Modulators of Innate Immunity

Borrelia gariniiInduces CXCL13 Production in Human Monocytes through Toll-Like Receptor 2

Role of Interleukin-1 and MyD88-Dependent Signaling in Rhinovirus Infection

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