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99
2003. Role of Toll-like receptors in pathogen recognition
- Clin. Microbiol. Rev
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Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3 (Mkk3)-deficient mice
- EMBO J. 18:1845
, 1999
"... The p38 mitogen-activated protein kinase (MAPK) pathway, like the c-Jun N-terminal kinase (JNK) MAPK pathway, is activated in response to cellular stress and inflammation and is involved in many fundamental biological processes. To study the role of the p38 MAPK pathway in vivo, we have used homolo ..."
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The p38 mitogen-activated protein kinase (MAPK) pathway, like the c-Jun N-terminal kinase (JNK) MAPK pathway, is activated in response to cellular stress and inflammation and is involved in many fundamental biological processes. To study the role of the p38 MAPK pathway in vivo, we have used homologous recombination in mice to inactivate the Mkk3 gene, one of the two specific MAPK kinases (MAPKKs) that activate p38 MAPK. Mkk3 -/-mice were viable and fertile; however, they were defective in interleukin-12 (IL-12) production by macrophages and dendritic cells. Interferon-γ production following immunization with protein antigens and in vitro differentiation of naive T cells is greatly reduced, suggesting an impaired type I cytokine immune response. The effect of the p38 MAPK pathway on IL-12 expression is at least partly transcriptional, since inhibition of this pathway blocks IL-12 p40 promoter activity in macrophage cell lines and IL-12 p40 mRNA is reduced in MKK3-deficient mice. We conclude that the p38 MAP kinase, activated through MKK3, is required for the production of inflammatory cytokines by both antigen-presenting cells and CD4 ⍣ T cells.
Yersinia V–Antigen Exploits Toll-like Receptor 2 and CD14 for Interleukin 10–mediated Immunosuppression
"... A characteristic of the three human-pathogenic Yersinia spp. (the plague agent Yersinia pestis and the enteropathogenic Yersinia pseudotuberculosis and Yersinia enterocolitica) is the expression of the virulence (V)-antigen (LcrV). LcrV is a released protein which is involved in contact-induced secr ..."
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Cited by 35 (2 self)
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A characteristic of the three human-pathogenic Yersinia spp. (the plague agent Yersinia pestis and the enteropathogenic Yersinia pseudotuberculosis and Yersinia enterocolitica) is the expression of the virulence (V)-antigen (LcrV). LcrV is a released protein which is involved in contact-induced secretion of yersinia antihost proteins and in evasion of the host’s innate immune response. Here we report that recombinant LcrV signals in a CD14- and toll-like receptor 2 (TLR2)dependent fashion leading to immunosuppression by interleukin 10 induction. The impact of this immunosuppressive effect for yersinia pathogenesis is underlined by the observation that TLR2-deficient mice are less susceptible to oral Y. enterocolitica infection than isogenic wildtype animals. In summary, these data demonstrate a new ligand specificity of TLR2, as LcrV is the first known secreted and nonlipidated virulence-associated protein of a Gram-negative bacterium using TLR2 for cell activation. We conclude that yersiniae might exploit host innate pattern recognition molecules and defense mechanisms to evade the host immune response. Key words: immunity • monocytes/macrophages • inflammation • bacterial proteins • immunosuppression D. Rost and N. Tvardovskaia contributed equally to this work. Address correspondence to Jürgen Heesemann, Max von Pettenkofer-
Crucial role of the interleukin 1 receptor family member T1/ST2 in T helper cell type 2-mediated lung mucosal immune responses
, 1999
"... T1/ST2 is an orphan receptor of unknown function that is expressed on the surface of murine T helper cell type 2 (Th2), but not Th1 effector cells. In vitro blockade of T1/ST2 signaling with an immunoglobulin (Ig) fusion protein suppresses both differentiation to and activation of Th2, but not Th1 e ..."
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Cited by 28 (3 self)
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T1/ST2 is an orphan receptor of unknown function that is expressed on the surface of murine T helper cell type 2 (Th2), but not Th1 effector cells. In vitro blockade of T1/ST2 signaling with an immunoglobulin (Ig) fusion protein suppresses both differentiation to and activation of Th2, but not Th1 effector populations. In a nascent Th2-dominated response, anti-T1/ST2 monoclonal antibody (mAb) inhibited eosinophil infiltration, interleukin 5 secretion, and IgE production. To determine if these effects were mediated by a direct effect on Th2 cells, we next used a murine adoptive transfer model of Th1- and Th2-mediated lung mucosal immune responses. Administration of either T1/ST2 mAb or T1/ST2-Ig abrogated Th2 cytokine production in vivo and the induction of an eosinophilic inflammatory response, but failed to modify Th1-mediated inflammation. Taken together, our data demonstrate an important role of T1/ST2 in Th2-mediated inflammatory responses and suggest that T1/ST2 may prove to be a novel target for the selective suppression of Th2 immune responses. Key words: inflammation • eosinophil • asthma • cytokines • immunoglobulin superfamily While the molecular basis underlying Th1 and Th2 differentiation still remains to be fully elucidated,
Transport of bacterial lipopolysaccharide to the Golgi apparatus
, 1999
"... Addition of lipopolysaccharide (LPS) to cells in the form of LPS–soluble (s)CD14 complexes induces strong cellular responses. During this process, LPS is delivered from sCD14 to the plasma membrane, and the cell-associated LPS is then rapidly transported to an intracellular site. This transport appe ..."
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Cited by 26 (0 self)
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Addition of lipopolysaccharide (LPS) to cells in the form of LPS–soluble (s)CD14 complexes induces strong cellular responses. During this process, LPS is delivered from sCD14 to the plasma membrane, and the cell-associated LPS is then rapidly transported to an intracellular site. This transport appears to be important for certain cellular responses to LPS, as drugs that block transport also inhibit signaling and cells from LPS-hyporesponsive C3H/HeJ mice fail to exhibit this transport. To identify the intracellular destination of fluorescently labeled LPS after its delivery from sCD14 into cells, we have made simultaneous observations of different organelles using fluorescent vital dyes or probes. Endosomes, lysosomes, the endoplasmic reticulum, and the Golgi apparatus were labeled using Texas red (TR)–dextran, LysoTracker ™ Red DND-99, DiOC6(3), and boron dipyrromethane (BODIPY)–ceramide, respectively. After 30 min, LPS did not colocalize with endosomes, lysosomes, or endoplasmic reticulum in polymorphonuclear leukocytes, although some LPS-positive vesicles overlapped with the endosomal marker, fluorescent dextran. On the other hand, LPS did appear to colocalize with two markers of the Golgi apparatus, BODIPY–ceramide and TRITC (tetramethylrhodamine isothiocyanate)–labeled cholera toxin B subunit. We further confirmed the localization of LPS
Toll-like receptor 9 mediates CpG-DNA signaling
- J. Leukoc. Biol. 71:538
, 2002
"... Abstract: Among the bacterial products known to activate the innate immune ‘1system is bacterial DNA. This activity resides within the nonmethyl-ated CpG motifs of the DNA and is recapitulated using appropriate synthetic CpG containing oli-godeoxynucleotides (CpG-ODN). TLR9-deficient mice were shown ..."
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Cited by 18 (0 self)
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Abstract: Among the bacterial products known to activate the innate immune ‘1system is bacterial DNA. This activity resides within the nonmethyl-ated CpG motifs of the DNA and is recapitulated using appropriate synthetic CpG containing oli-godeoxynucleotides (CpG-ODN). TLR9-deficient mice were shown to exhibit a nonresponsive phe-notype-to-bacterial DNA and CpG-ODN. Here, we describe a model system to further characterize CpG-ODN and TLR9 interactions using ectopically expressed TLR9 in HEK293 cells. Expression of TLR9 confers cellular responsiveness to CpG-ODN but not to the other bacterial products. Previous studies identified species-specific CpG-containing sequences; here, we show that expression of mu-rine TLR9 favors responses to CpG-ODN motifs specific to mouse cells, and expression of human TLR9 favors CpG-ODN known to preferentially activate human cells. Response patterns to various CpG-ODN motifs were parallel when cells contain-ing an ectopically expressed TLR9 and endogenous receptor were compared. Here, we also show that TLR9 acts at the cell surface and engages an intra-cellular signaling pathway that includes MyD88,
Synergistic action of pro-inflammatory agents: cellular and molecular aspects
- J. Leukocyte
"... Abstract: Generation of an inflammatory response is a complex process involving multiple factors acting in parallel and in concert. Viruses, parasites, and bacteria, particularly lipopolysaccharide (LPS), a component of the cell wall of gramnegative bacteria, act cooperatively with the cytokine inte ..."
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Abstract: Generation of an inflammatory response is a complex process involving multiple factors acting in parallel and in concert. Viruses, parasites, and bacteria, particularly lipopolysaccharide (LPS), a component of the cell wall of gramnegative bacteria, act cooperatively with the cytokine interferon (IFN)- � to induce many of the genes involved in inflammation. In addition, these components synergistically induce secretion of tumor necrosis factor � (TNF-�), which also synergizes strongly with IFN-�. The molecular mechanisms underlying the synergistic gene induction discussed in this review involve cooperative activation of transcription factors. IFN-�-activated signal transducer and activator of transcription 1 and interferon regulatory factor-1 function synergistically with nuclear factor �B activated by LPS and TNF-�. In addition, cross-talk between the signal transduction pathways upstream of the activation of the transcription factors contributes to generation of the synergistic action. Cooperative activity of proinflammatory agents profoundly influences the immune response to infections and the efficiency of cellular clearance mechanisms. J. Leukoc. Biol.
Toll receptors: an expanding role in our understanding of human disease
- J Leukoc Biol
"... Abstract: Toll receptor proteins in Drosophila are involved in establishing the dorsal-ventral axis in embryogenesis as well as participating in the innate immune response to invading pathogens. The basic mediators of this response show striking similarities in plants, insects, and vertebrates. The ..."
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Abstract: Toll receptor proteins in Drosophila are involved in establishing the dorsal-ventral axis in embryogenesis as well as participating in the innate immune response to invading pathogens. The basic mediators of this response show striking similarities in plants, insects, and vertebrates. The cytoplasmic signaling cascade is exemplified by the human interleukin-1 receptor complex (IL-1R), resulting in transcriptional activation of effector proteins through nuclear factor-�B (NF-�B). Six mammalian/human Toll-like receptors (TLR) have been described to date. The TLRs share the IL-1R cytoplasmic signaling cascade but are distinguished by their extracellular leucine-rich repeat (LRR) structure. The LRR superfamily comprises a diverse group of proteins, including a cohort involved in transmembrane signaling. Two of the human TLRs (TLR2, TLR4) have been shown to be involved in the innate response to bacterial pathogens and appear to provide a link between the innate and adaptive immune response. A better understanding of this response may provide improved therapeutic modalities in the treatment of bacterial and fungal sepsis, which continues to be a significant source of morbidity and mortality worldwide. In addition, similar to Drosophila, Toll receptors and related proteins in the LRR superfamily may also be involved in human development, as well as in noninfectious human disease. J. Leukoc.
Toll-like receptor 2 mediates alveolar macrophage response to Pneumocystis murina
- Infect. Immun
, 2006
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Cited by 14 (1 self)
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This article cites 53 articles, 40 of which can be accessed free
Toll-like receptor 2-mediated signaling requirements for Francisella tularensis live vaccine strain infection of murine macrophages
- Infect. Immun
, 2007
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Cited by 13 (4 self)
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These include: This article cites 59 articles, 32 of which can be accessed free at:
