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At least 1,279 records · Page 71Linked to original sources
PubMed2005

TICAM-1 and TICAM-2: toll-like receptor adapters that participate in induction of type 1 interferons.

Toll-like receptor (TLR) 3 and 4 mediate the expression of many genes, including NF-kappaB- and interferon-regulatory factor (IRF)-3/interferon (IFN)-inducible genes, in macrophages and dendritic cells (DCs) in response to their ligand stimuli, polyI:C and lipopolysaccharide (LPS). Toll-IL-1 receptor homology domain (TIR)-containing adapter molecule 1 (TICAM-1) facilitates expression of IFN-inducible genes via TLR3. Although MyD88 and Mal/TIRAP adapters function downstream of TLR4, they barely induce IFN-beta. In addition, DC maturation as well as IFN-beta induction are largely independent of MyD88 and Mal/TIRAP. TICAM-1 is the functional adapter for both TLR3 and TLR4 that induces type 1 IFN and MyD88-independent DC maturation. In LPS-mediated TLR4 activation, a complex of TICAM-1 and an additional TLR4-binding adapter serves as the adapter. We named this TLR4-TICAM-1-bridging adapter TICAM-2. Our results reveal the details of MyD88-independent pathways which separately recruit the distinct adapters downstream of TLR3 and TLR4 and variations of the TLR output are in part regulated by the two additional adapters in DCs.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Candida albicans induces selectively transcriptional activation of cyclooxygenase-2 in HeLa cells: pivotal roles of Toll-like receptors, p38 mitogen-activated protein kinase, and NF-kappa B.

Candidiasis, in its mucocutaneous form as well as in an invasive form, is frequently associated with high morbidity. PGE(2), which is generated by enzymatic activity of cyclooxygenases (COXs) 1 and 2, has been shown to trigger morphogenesis in Candida albicans. In the present study, we investigated whether C. albicans altered COX-2 expression in HeLa cells. RT-PCR and Western blot analyses revealed a time-dependent biphasic behavior of COX-2 mRNA expression and COX-2 protein level. COX-1 protein remained unaffected. Neutralization with Abs against Toll-like receptors (TLR) 2 and 4 inhibited the Candida-induced production of PGE(2), suggesting a vital role for TLRs in the recognition and signaling in mammalian cells upon infection with C. albicans. Transient transfections with COX-2 promoter-luciferase construct and various inhibitors of mitogen-activated protein kinases (MAPK), such as protein kinase C (PKC) inhibitor GF203190X, p38(MAPK) inhibitor SB203109, and extracellular-regulated kinases 1 and 2 inhibitor PD98509 showed that C. albicans up-regulates selectively COX-2, but not COX-1, through p38(MAPK) and PKC pathways. No involvement of other stress kinases, e.g., c-Jun NH(2)-terminal kinase and extracellular-regulated kinases 1 and 2, was observed. Transient transfection of NF-kappaB promoter construct and dominant negative plasmid of IkappaBbeta kinase showed that COX-2 transcription is mediated through p38(MAPK) and NF-kappaB pathways. That NF-kappaB up-regulates p38(MAPK) is novel and is in contradiction to earlier reports in which NF-kappaB was shown to inhibit p38(MAPK). In conclusion, multiple converging signaling pathways, involving TLRs followed by PKC, p38(MAPK), and/or NF-kappaB, are triggered by C. albicans in activation of COX-2 gene.

Candida albicans↗
PubMed2005

TLR4 and Toll-IL-1 receptor domain-containing adapter-inducing IFN-beta, but not MyD88, regulate Escherichia coli-induced dendritic cell maturation and apoptosis in vivo.

Dendritic cells (DC) are short-lived, professional APCs that play a central role in the generation of adaptive immune responses. Induction of efficient immune responses is dependent on how long DCs survive in the host. Therefore, the regulation of DC apoptosis in vivo during infection remains an important question that requires further investigation. The impact of Escherichia coli bacteremia on DCs has never been analyzed. We show here that i.v. or i.p. administration of live or heat-killed E. coli in mice induces splenic DC migration, maturation, and apoptosis. We further characterize which TLR and Toll-IL-1R (TIR)-containing adaptor molecules regulate these processes in vivo. In this model, DC maturation is impaired in TLR2(-/-), TLR4(-/-) and TIR domain-containing adapter-inducing IFN-beta (TRIF)(-/-) mice. In contrast, DC apoptosis is reduced only in TLR4(-/-) and TRIF(-/-) mice. As expected, DC apoptosis induced by the TLR4 ligand LPS is also abolished in these mice. Injection of the TLR9 ligand CpG-oligodeoxynucleotide (synthetic bacterial DNA) induces DC migration and maturation, but only modest DC apoptosis when compared with LPS and E. coli. Together, these results suggest that E. coli bacteremia directly impacts on DC maturation and survival in vivo through a TLR4-TRIF-dependent signaling pathway.

Adaptor Proteins, Signal Transducing↗
PubMed2005

[Expression of CD14 and Toll-like receptor 4 on Kupffer cells and its role in ischemia-reperfusion injury on rat liver graft].

OBJECTIVE: To study the expression of lipopolysaccharide (LPS) receptor CD14 and Toll-like receptor 4 (TLR4) on Kupffer cells and its role in ischemia-reperfusion injury (IRI) on rat liver graft. METHODS: The Kupffer cells following IRI were isolated and divided into control, ischemia-reperfusion (IR), and anti-CD14 antibody group. The mRNA and protein expression of CD14 and TLR4, nuclear factor kappa B (NF-kappaB) activity and TNF-alpha level in supernatant were measured. RESULTS: The mRNA and protein expression of CD14 and TLR4 in IR group were significantly higher than those in control group (P < 0.01). The NF-kappaB activity and TNF-alpha level in IR group were significantly higher than those in control group (P < 0.01), and they greatly decreased after anti CD14 antibody treatment (compared with IR group, P < 0.05), but were still significantly higher than those in control group (P < 0.01). CONCLUSIONS: LPS following IRI could up-regulate CD14 and TLR4 gene and protein expression on Kupffer cells, and subsequently activate NF-kappaB to produce cytokines, but other signal transduction pathways might also participate in the IRI.

Animals↗
PubMed2006

Interleukin-18 secretion and Th1-like cytokine responses in human peripheral blood mononuclear cells under the influence of the toll-like receptor-5 ligand flagellin.

Flagellin is the major protein component of the flagella from motile bacteria and was identified as the ligand for toll-like receptor (TLR)-5. Whereas its effects on epithelial cells have been studied in detail, activation of human peripheral blood mononuclear cells (PBMC) by flagellin is characterized only partially. By using the recombinant protein of Salmonella muenchen we confirm the proinflammatory nature of flagellin as detected by nuclear factor-kappaB activation and interleukin (IL)-8 production. Aim of the current study was to elucidate in PBMC effects of flagellin on IL-18 and Th1-like cytokine responses. We report that flagellin in pathophysiologically relevant concentrations augmented release of mature IL-18 by THP-1 monocytes, PBMC, and whole blood stimulated with nigericin or by ATP-mediated P2X7 purinergic receptor activation. Further key functions of the IL-18/IL-12/interferon-gamma (IFNgamma) pathway were upregulated by flagellin. Flagellin synergized with IL-12 for production of IFN-gamma and augmented secretion of interferon-inducible protein-10, a CXC-chemokine that is key to the generation of Th1-type responses. In contrast, neither IL-18-binding protein nor IL-4 was affected. Taken together, the present data demonstrate for the first time that flagellin at concentrations that are detectable in the blood compartment during sepsis efficiently enhances the IL-18/IL-12/IFNgamma pathway and thus Th1-like cytokine responses in PBMC.

Adenosine Triphosphate↗
PubMed2004

Direct bacterial protein PAMP recognition by human NK cells involves TLRs and triggers alpha-defensin production.

Although human CD56(+)CD3(-) natural killer (NK) cells participate in immune responses against microorganisms, their capacity to directly recognize and be activated by pathogens remains unclear. These cells encode members of the Toll-like receptor (TLR) family, involved in innate cell activation on recognition of pathogen-associated molecular patterns (PAMPs). We therefore evaluated whether the 2 bacterial protein PAMPs, the outer membrane protein A from Klebsiella pneumoniae (KpOmpA) and flagellin, which signal through TLR2 and TLR5, respectively, may directly stimulate human NK cells. These proteins induce interferon-gamma (IFN-gamma) production by NK cells and synergize with interleukin-2 (IL-2) and proinflammatory cytokines in PAMP-induced activation. Similar results were obtained using CD56(+)CD3(+) (NKR-expressing) T cells. NK cells from TLR2(-/-) mice fail to respond to KpOmpA, demonstrating TLR involvement in this effect. Defensins are antimicrobial peptides expressed mainly by epithelial cells and neutrophils that disrupt the bacterial membrane, leading to pathogen death. We show that NK cells and NKR-expressing T cells constitutively express alpha-defensins and that KpOmpA and flagellin rapidly induce their release. These data demonstrate for the first time that highly purified NK cells directly recognize and respond to pathogen components through TLRs and evidence defensins as a novel and direct cytotoxic pathway involved in NK cell-mediated protection against microorganisms.

Animals↗
PubMed2005

Regulation of cellular caveolin-1 protein expression in murine macrophages by microbial products.

Previously, we reported that expression of caveolin-1 in elicited peritoneal mouse macrophages was up-regulated by remarkably low (1.0-pg/ml) concentrations of Escherichia coli O111 lipopolysaccharide (LPS). Here we report that increases in caveolin-1 expression are manifested by different types of LPS, LPS-mimetic taxol, and heat-killed E. coli and to a much lesser extent by zymosan, polysaccharide-peptidoglycan, and heat-killed Staphylococcus aureus. Rhodobacter sphaeroides lipid A (RsDPLA) could not induce caveolin-1 expression in macrophages. Interestingly, polymyxin B (5 microg/ml) and RsDPLA show only a limited capacity to inhibit LPS-induced caveolin-1 expression. These findings suggest that expression of caveolin-1 in response to LPS may only partially be dependent upon lipid A. Recombinant tumor necrosis factor alpha marginally induces caveolin-1, suggesting that the ability of LPS to regulate caveolin-1 is not mediated primarily through an autocrine/paracrine mechanism involving this cytokine. Under conditions in which cellular levels of caveolin-1 are profoundly induced, no significant changes in TLR4 expression are observed. Of interest, caveolin-1 appears to localize to two cellular compartments, one associated with lipid rafts and a second associated with TLR4. Gamma interferon treatment inhibits the induction of caveolin-1 by LPS in macrophages. Inhibition of the p38 kinase-dependent pathway, but not the extracellular signal-regulated kinase pathway, effectively reduced the ability of LPS to mediate caveolin-1 up-regulation. Lactacystin, a potent inhibitor of the proteasome pathway, significantly modulates LPS-independent caveolin-1 expression, and lactacystin inhibits LPS-triggered caveolin-1 responses. These studies suggest that caveolin-1 up-regulation in response to LPS is likely to be proteasome dependent and triggered through the p38 kinase pathway.

Animals↗
PubMed2005

Differential involvement of BB loops of toll-IL-1 resistance (TIR) domain-containing adapter proteins in TLR4- versus TLR2-mediated signal transduction.

TLRs sense pathogens and transmit intracellular signals via the use of specific adapter proteins. We designed a set of "blocking peptides" (BPs) comprised of the 14 aa that correspond to the sequences of the BB loops of the four known Toll-IL-1 resistance (TIR) domain-containing adapter proteins (i.e., MyD88, TIR domain-containing adapter inducing IFN-beta (TRIF), TRIF-related adapter molecule (TRAM), and TIR-domain containing adapter protein (TIRAP)) linked to the cell-penetrating segment of the antennapedia homeodomain. LPS (TLR4)-mediated gene expression, as well as MAPK and transcription factor activation associated with both MyD88-dependent and -independent signaling pathways, were disrupted by all four BPs (TRAM approximately MyD88 > TRIF > TIRAP), but not by a control peptide. In contrast, none of the BPs inhibited TLR2-mediated activation of MAPKs. Only the MyD88 BP significantly blocked Pam3Cys-induced IL-1beta mRNA; however, the inhibitory effect was much less than observed for LPS. Our data suggest that the interactions required for a fully functional TLR4 signaling "platform" are disrupted by these BPs, and that the adapter BB loops may serve distinct roles in TLR4 and TLR2 signalosome assembly.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Recognition of single-stranded RNA viruses by Toll-like receptor 7.

Viral infection of mammalian host results in the activation of innate immune responses. Toll-like receptors (TLRs) have been shown to mediate the recognition of many types of pathogens, including viruses. The genomes of viruses possess unique characteristics that are not found in mammalian genomes, such as high CpG content and double-stranded RNA. These genomic nucleic acids serve as molecular signatures associated with viral infections. Here we show that TLR7 recognizes the single-stranded RNA viruses, vesicular stomatitis virus and influenza virus. The recognition of these viruses by plasmacytoid dendritic cells and B cells through TLR7 results in their activation of costimulatory molecules and production of cytokines. Moreover, this recognition required intact endocytic pathways. Mice deficient in either the TLR7 or the TLR adaptor protein MyD88 demonstrated reduced responses to in vivo infection with vesicular stomatitis virus. These results demonstrate microbial ligand recognition by TLR7 and provide insights into the pathways used by the innate immune cells in the recognition of viral pathogens.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Self- and nonself-recognition by C-type lectins on dendritic cells.

Dendritic cells (DCs) are highly efficient antigen-presenting cells (APCs) that collect antigen in body tissues and transport them to draining lymph nodes. Antigenic peptides are loaded onto major histocompatibility complex (MHC) molecules for presentation to naive T cells, resulting in the induction of cellular and humoral immune responses. DCs take up antigen through phagocytosis, pinocytosis, and endocytosis via different groups of receptor families, such as Fc receptors for antigen-antibody complexes, C-type lectin receptors (CLRs) for glycoproteins, and pattern recognition receptors, such as Toll-like receptors (TLRs), for microbial antigens. Uptake of antigen by CLRs leads to presentation of antigens on MHC class I and II molecules. DCs are well equipped to distinguish between self- and nonself-antigens by the variable expression of cell-surface receptors such as CLRs and TLRs. In the steady state, DCs are not immunologically quiescent but use their antigen-handling capacities to maintain peripheral tolerance. DCs are continuously sampling and presenting self- and harmless environmental proteins to silence immune activation. Uptake of self-components in the intestine and airways are good examples of sites where continuous presentation of self- and foreign antigens occurs without immune activation. In contrast, efficient antigen-specific immune activation occurs upon encounter of DCs with nonself-pathogens. Recognition of pathogens by DCs triggers specific receptors such as TLRs that result in DC maturation and subsequently immune activation. Here we discuss the concept that cross talk between TLRs and CLRs, differentially expressed by subsets of DCs, accounts for the different pathways to peripheral tolerance, such as deletion and suppression, and immune activation.

Animals↗
PubMed2004

Bruton's tyrosine kinase (Btk)-the critical tyrosine kinase in LPS signalling?

The discovery of the Toll-like receptors (TLRs) has revolutionised the field of innate immunity. One unresolved question regarding LPS signalling is whether there is a role for tyrosine kinases downstream of the LPS receptor. Studies in mice deficient in Bruton's tyrosine kinase have previously shown that they are defective in their responses to LPS. Further investigation into the role of Btk in LPS signalling has directly implicated Btk downstream of TLR4, both with respect to p38 MAPK activation and activation of the transcription factor NFkappaB. In fact Btk is activated by LPS and has been shown to directly bind TLR4 and the key proximal signalling proteins involved in LPS-induced NFkappaB activation, MyD88, Mal and IRAK-1. These recent findings point to a direct role for Btk in LPS signal transduction and raise interesting questions regarding the mode of activation of Btk following LPS stimulation and the precise nature of the pathways activated downstream of Btk. A better understanding of how Btk functions in LPS signalling will have important implications for inflammatory and autoimmune disorders and therapies thereof.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed2005

Cutting Edge: NF-kappaB-activating kinase-associated protein 1 participates in TLR3/Toll-IL-1 homology domain-containing adapter molecule-1-mediated IFN regulatory factor 3 activation.

TLRs signal the presence of microbial patterns and activate transcription factors. In TLR3 and TLR4, the adapter Toll-IL-1R homology domain-containing adapter molecule (TICAM-1) (also called Toll/IL-1R domain-containing adapter inducing IFN-beta (TRIF)) mediates IFN regulatory factor 3 (IRF3) phosphorylation followed by IFN-beta production. The regulatory subunit TNFR-associated factor family member-associated NF-kappaB activator (TANK) couples with the kinase complex IkappaB kinase-related kinase epsilon/NF-kappaB-activating kinase (NAK) (TANK-binding kinase 1 (TBK1)) that involveTICAM-1-dependent IFN-beta induction. There are several TANK-homologous proteins. We tested whether TICAM-1 binds and coprecipitates with TANK or its family proteins. The results are: 1) the TANK family protein NAK-associated protein 1 (NAP1), but not TANK, coprecipitates withTICAM-1; 2) NAP1 overexpression markedly enhances TBK1-mediated IFN-beta promoter activation; 3) a dominant-negative form, NAP (158-270), suppresses IRF3 activation in response to poly(I:C) or LPS; 4) RNA interference targeting of the NAP1 message results in a failure of poly(I:C)-mediated IRF3 polymerization and IFN-beta production. Thus, NAP1 is the kinase subunit responsible for TLR3/4-mediated IFN-beta induction in the TICAM-1 pathway.

Adaptor Proteins, Signal Transducing↗
PubMed1992

Connectin: a homophilic cell adhesion molecule expressed on a subset of muscles and the motoneurons that innervate them in Drosophila.

Each abdominal hemisegment in the Drosophila embryo contains a stereotyped array of 30 muscles, each specifically innervated by one or a few motoneurons. We screened 11,000 enhancer trap lines, isolated several expressing beta-galactosidase in small subsets of muscle fibers prior to innervation, and identified two of these as inserts in connectin and Toll, members of the leucine-rich repeat gene family. Connectin contains a signal sequence, ten leucine-rich repeats, and a putative phosphatidylinositol membrane linkage; in S2 cells, connectin can mediate homophilic cell adhesion. Connectin is expressed on the surface of eight muscles, the motoneurons that innervate them, and several glial cells along the pathways leading to them. During synapse formation, the protein localizes to synaptic sites; afterward, it largely disappears. Thus, connectin is a novel cell adhesion molecule whose expression suggests a role in target recognition.

Amino Acid Sequence↗
PubMed2005

Yersinia outer proteins: role in modulation of host cell signaling responses and pathogenesis.

A type III secretion system (TTSS) is encoded on a virulence plasmid that is common to three pathogenic Yersinia species: Y. enterocolitica, Y. pseudotuberculosis, and Y. pestis. Pathogenic Yersinia species require this TTSS to survive and replicate within lymphoid tissues of their animal or human hosts. A set of pathogenicity factors, including those known as Yersinia outer proteins (Yops), is exported by this system upon bacterial infection of host cells. Two translocator Yops (YopB and YopD) insert into the host plasma membrane and function to transport six effector Yops (YopO, YopH, YopM, YopT, YopJ, and YopE) into the cytosol of the host cell. Effector Yops function to counteract multiple signaling responses in the infected host cell. The signaling responses counteracted by Yops are initiated by phagocytic receptors, Toll-like receptors, translocator Yops, and additional mechanisms. Innate and adaptive immune responses are thwarted as a consequence of Yop activities. A biochemical function for each effector Yop has been established, and the importance of these proteins for the pathogenesis process is being elucidated. This review focuses on the biochemical functions of Yops, the signaling pathways they modulate, and the role of these proteins in Yersinia virulence.

Animals↗
PubMed2002

Lipopolysaccharides from periodontopathic bacteria Porphyromonas gingivalis and Capnocytophaga ochracea are antagonists for human toll-like receptor 4.

Toll-like receptors (TLRs) 2 and 4 have recently been identified as possible signal transducers for various bacterial ligands. To investigate the roles of TLRs in the recognition of periodontopathic bacteria by the innate immune system, a Chinese hamster ovary (CHO) nuclear factor-kappaB (NF-kappaB)-dependent reporter cell line, 7.7, which is defective in both TLR2- and TLR4-dependent signaling pathways was transfected with human CD14 and TLRs. When the transfectants were exposed to freeze-dried periodontopathic bacteria, Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Capnocytophaga ochracea, and Fusobacterium nucleatum, and a non-oral bacterium, Escherichia coli, all species of the bacteria induced NF-kappaB-dependent CD25 expression in 7.7/huTLR2 cells. Although freeze-dried A. actinomycetemcomitans, F. nucleatum, and E. coli also induced CD25 expression in 7.7/huTLR4 cells, freeze-dried P. gingivalis did not. Similarly, lipopolysaccharides (LPS) extracted from A. actinomycetemcomitans, F. nucleatum, and E. coli induced CD25 expression in 7.7/huTLR4 cells, but LPS from P. gingivalis and C. ochracea did not. Furthermore, LPS from P. gingivalis and C. ochracea attenuated CD25 expression in 7.7/huTLR4 cells induced by repurified LPS from E. coli. LPS from P. gingivalis and C. ochracea also inhibited the secretion of interleukin-6 (IL-6) from U373 cells, the secretion of IL-1beta from human peripheral blood mononuclear cells, and ICAM-1 expression in human gingival fibroblasts induced by repurified LPS from E. coli. These findings indicated that LPS from P. gingivalis and C. ochracea worked as antagonists for human TLR4. The antagonistic activity of LPS from these periodontopathic bacteria may be associated with the etiology of periodontal diseases.

Aggregatibacter actinomycetemcomitans↗
PubMed2003

CpG directly induces T-bet expression and inhibits IgG1 and IgE switching in B cells.

CpG DNA has immunomodulatory effects, such as the suppression of allergic responses mediated by type II T cell help (T(H)2). Here we report that CpG, but not lipopolysaccharide (LPS), rapidly induces expression of T-bet mRNA in purified B cells. Up-regulation of T-bet by CpG is abrogated in mice deficient in Toll-like receptor 9 (TLR9) and MyD88, but remains intact in B cells deficient in STAT1 (signal transducer and activator of transcription 1). Interleukin 12 (IL-12) alone does not up-regulate T-bet mRNA, but greatly enhances CpG-induced T-bet expression. Furthermore, CpG inhibits immunoglobulin G1 (IgG1) and IgE switching induced by IL-4 and CD40 signaling in purified B cells, and this effect correlates with up-regulation of T-bet. Thus, CpG triggers anti-allergic immune responses by directly regulating T-bet expression via a signaling pathway in B cells that is dependent upon TLR9, independent of interferon-gamma (IFN-gamma)-STAT1 and synergistic with IL-12.

Animals↗
PubMed1994

Activation of the kinase Pelle by Tube in the dorsoventral signal transduction pathway of Drosophila embryo.

The concentration of Dorsal protein in the nucleus determines cell fate along the dorsoventral axis of the Drosophila embryo. The dorsal-group genes and the cactus gene are required for production and transmission of a localized signal on the ventral side of the embryo which determines the position of the highest nuclear concentration of Dorsal protein. The ventralizing signal produced in somatic cells is transmitted through the perivitelline space to the integral membrane protein Toll. Inside the embryo it leads to dissociation of the cytoplasmic Dorsal-Cactus complex and subsequent nuclear localization of Dorsal protein. Two components are known to mediate the signal transduction between Toll and Dorsal-Cactus: Pelle, a serine/threonine protein kinase, and Tube, a protein with an unknown biochemical activity. Here we construct gain-of-function alleles of pelle and tube and show that pelle functions downstream of tube. In addition, Pelle and Tube interact directly with one another. We propose that Tube is a direct activator of the protein kinase Pelle.

Alleles↗
PubMed2005

House dust extracts elicit Toll-like receptor-dependent dendritic cell responses.

BACKGROUND: Laboratory and epidemiological studies have provided indirect but compelling evidence that Toll-like receptors (TLRs) play an important role in innate host responsiveness to ambient immunostimulatory factors. However, little direct evidence exists. OBJECTIVE: To determine whether house dust extracts activate dendritic cells by TLR-dependent mechanisms. METHODS: In initial studies, bone marrow-derived dendritic cells were cultured with sterile house dust extracts, and cytokine production and costimulatory molecule expression were evaluated. In additional experiments, the TLR dependence of these responses was assessed. RESULTS: House dust extract-activated bone marrow-derived dendritic cells were found to produce IL-6 and IL-12 in a concentration-dependent manner and to increase their expression of CD40, CD80, CD86, and MHC class II molecules. Furthermore, correlations were seen between the relative bioactivities of house dust extracts and their endotoxin levels. Finally, bone marrow-derived dendritic cells from TLR (2, 4, and 9)-deficient mice all demonstrated attenuated responses, and MyD88 deficient bone marrow-derived dendritic cells were almost completely nonresponsive to house dust extracts. CONCLUSION: These investigations provide direct evidence that TLR signaling pathways play a central role in at least a subset of dendritic cell responses to noninfectious factors ubiquitous in living environments.

Animals↗