Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “TOLL pathway”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,297 records · Page 72Linked to original sources
PubMed2002

Differences in LPS-induced activation of bronchial epithelial cells (BEAS-2B) and type II-like pneumocytes (A-549).

Lipopolysaccharide (LPS) as a major component of the outer membrane of gram-negative bacteria stimulates various cells to initiate a signalling cascade which ultimately leads to cell activation and expression of immunoregulatory or inflammatory cytokines. The human respiratory epithelium is an important environmental interface, but differences in LPS-induced cell activation between bronchial and alveolar epithelial cells have not yet been investigated in detail. First, the expression of Toll-like receptors (TLRs), as pattern-recognition receptors, was investigated for the bronchial epithelial cells and type II-like pneumocytes, demonstrating that they fulfil the prerequisites for LPS signalling. Thereafter, the effects of LPS, soluble CD14 (sCD14) and LPS-binding protein (LBP) on the release of interleukin-6 (IL-6) and IL-8 were studied. In the presence of LPS, sCD14 induced a significant and concentration-dependent cytokine release in type II-like pneumocytes, whereas the response of bronchial epithelial cells to sCD14 stimulation was low, implicating sCD14-independent activation mechanisms. Furthermore, LBP revealed inhibitory effects on the activation of alveolar epithelial cells, which may represent a novel local defence mechanism during gram-negative infection. We conclude that distinct pathways exist for LPS-induced activation of bronchial and alveolar epithelial cells.

Acute-Phase Proteins↗
PubMed2005

Toll-like receptor 2 (TLR2) mediates intracellular signalling in human keratinocytes in response to Malassezia furfur.

Toll-like receptors (TLRs) are crucial players in the innate immune response to microbial invaders. The lipophilic yeast Malassezia furfur has been implicated in the triggering of scalp lesions in psoriasis. The aim of the present study was to assess the role of TLRs in the defence against M. furfur infection. The expression of the myeloid differentiation factor 88 (MyD88) gene, which is involved in the signalling pathway of many TLRs, was also analysed. In addition, a possible correlation of antimicrobial peptides of the beta-defensin family to TLRs was tested. Human keratinocytes infected with M. furfur and a variety of M. furfur-positive psoriatic skin biopsies were analysed by RT-PCR, for TLRs, MyD88, human beta-defensin 2 (HBD-2), HBD-3 and interleukin-8 (IL-8) mRNA expression. When keratinocytes were infected with M. furfur, an up-regulation for TLR2, MyD88, HBD-2, HBD-3 and IL-8 mRNA was demonstrated, compared to the untreated cells. The same results were obtained when psoriatic skin biopsies were analysed. The M. furfur-induced increase in HBD-2 and IL-8 gene expression is inhibited by anti-TLR2 neutralising antibodies, suggesting that TLR2 is involved in the M. furfur-induced expression of these molecules. These findings suggest the importance of TLRs in skin protection against fungi and the importance of keratinocytes as a component of innate immunity.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Toll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment.

Toll-like receptors (TLRs) are best known for their ability to recognize microbial or viral components and initiate innate immune responses. We showed here that TLRs and their coreceptors were expressed by multipotential hematopoietic stem cells, whose cell cycle entry was triggered by TLR ligation. TLR expression also extended to some of the early hematopoietic progenitors, although not the progenitor cells dedicated to megakaryocyte and erythroid differentiation. TLR signaling via the Myd88 adaptor protein drove differentiation of myeloid progenitors, bypassing some normal growth and differentiation requirements, and also drove lymphoid progenitors to become dendritic cells. CD14 contributed to the efficiency of lipopolysaccharide (LPS) recognition by stem and progenitor cells, and LPS interacted directly with the TLR4/MD-2 complex on these cells in bone marrow. Thus, the preferential pathogen-mediated stimulation of myeloid differentiation pathways may provide a means for rapid replenishment of the innate immune system during infection.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Toll-like receptor 2-mediated gene expression in epithelial cells during Helicobacter pylori infection.

BACKGROUND: Helicobacter pylori is the major pathogen causing chronic gastritis and peptic ulcer disease and is closely linked to gastric malignancy. We have previously shown that H. pylori-induced NF-(kappa)B activation and interleukin (IL)-8 secretion are mediated by Toll-like receptor (TLR) 2 in epithelial cells. However, the TLR2-mediated global gene expression profile of the epithelial cell during H. pylori infection is still unknown. The goal of this study was to identify TLR2-regulated genes in epithelial cells induced by H. pylori. MATERIALS AND METHODS: The HEK293 and HEK-TLR2 cells were cocultured with H. pylori 26695 for 6 hours. Total RNA was extracted and hybridized to the Affymetrix human U133A microarray chipset, which contains 22,283 total probe sets including 14,285 genes. Data analyses were performed using affymetrix suite 5 software. The expression of selected genes in gastric epithelial cells AGS and MKN45 was monitored by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: Forty-six genes, contained in 57 probe sets, were induced > 2-fold and three genes (five probe sets) decreased > 2-fold by H. pylori infection of HEK293 cells. Fifty-four genes, contained in 69 probe sets, were induced > 2-fold, whereas only 1 gene was repressed > 2-fold in H. pylori-infected HEK-TLR2 cells. Comparisons of genes induced in HEK293 or HEK-TLR2 cells identified 28 genes whose expression was dependent on the presence of TLR2. Seventeen genes were selected and their expression was assessed using the quantitative RT-PCR in gastric epithelial cells during H. pylori infection. Eight of the 17 genes showed distinct expression patterns in AGS and MKN45 cells after H. pylori stimulation. CONCLUSIONS: The current study investigated the TLR2-mediated global gene changes after H. pylori stimulation in the epithelial cell system. This approach will be helpful in identifying genes whose expression is mediated by specific TLRs and in determining the cellular responses that are responsible for diverse signal pathways during H. pylori infection.

Cell Line↗
PubMed2006

Involvement of Toll-like receptor 5 in the recognition of flagellated bacteria.

Toll-like receptors (TLRs) are key components of the immune system that detect microbial infection and trigger antimicrobial host defense responses. TLR5 is a sensor for monomeric flagellin, which is a component of bacterial flagella known to be a virulence factor. In this study we generated TLR5-deficient mice and investigated the role of TLR5 signaling in the detection of flagellin and antibacterial immune responses to Salmonella typhimurium and Pseudomonas aeruginosa. We found that TLR5 is essential for the recognition of bacterial flagellin both in vivo and ex vivo. TLR5 contribution to antibacterial host response to i.p. infection with S. typhimurium or intranasal administration of P. aeruginosa may be masked by TLR4 or other sensing mechanisms. By using radiation bone marrow chimera, we showed that upon i.p. injection of flagellin immune responses are mediated by lymphoid cells, whereas resident cells are required for the initiation of response upon intranasal flagellin administration. These results suggest that flagellin recognition in different organs is mediated by distinct TLR5-expressing cells and provide insights into the cooperation of the TLR5 and TLR4 signaling pathways used by the innate immune system in the recognition of bacterial pathogens.

Animals↗
PubMed2006

ABIN-2 is required for optimal activation of Erk MAP kinase in innate immune responses.

The TPL-2 MEK kinase is essential for activation of the Erk MAP kinase pathway during innate immune responses. TPL-2 is found in complex with ABIN-2 (A20-binding inhibitor of NF-kappaB 2). Here, using antigen-presenting cells from ABIN-2-deficient mice, we show that ABIN-2 was required for optimal activation of Erk induced by receptors that signal via TPL-2, including Toll-like receptor 4 and tumor necrosis factor receptor 1 in macrophages, and CD40 in B cells. ABIN-2 was necessary for the maintenance of TPL-2 protein stability. In contrast, ABIN-2 deficiency did not affect agonist-induced regulation of transcription factor NF-kappaB. Stimulation of ABIN-2-deficient macrophages via Toll-like receptor 4 showed that different thresholds of Erk signaling were required for optimal induction of tumor necrosis factor and interleukin 1beta. Thus, ABIN-2 acts to positively regulate the Erk signaling potential by stabilizing TPL-2.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Pneumocystis carinii cell wall beta-glucans initiate macrophage inflammatory responses through NF-kappaB activation.

beta-Glucans are major structural components of fungi. We have recently reported that the pathogenic fungus Pneumocystis carinii assembles a beta-glucan-rich cell wall that potently activates alveolar macrophages to release pro-inflammatory cytokines and chemokines. Purified P. carinii beta-glucans predictably induce both cytokine generation and associated neutrophilic lung inflammation. Herein, we demonstrate that P. carinii beta-glucan-induced macrophage stimulation results from activation of NF-kappaB. Although analogous to macrophage activation induced by bacterial lipopolysaccharide (LPS), P. carinii beta-glucan-induced macrophage NF-kappaB activation exhibits distinctly different kinetics, with slower induction and longer duration compared with LPS stimulation. Macrophage activation in response to P. carinii beta-glucan was also substantially inhibited with the NF-kappaB antagonist pyrrolidine dithiocarbamate. In addition to different kinetics of NF-kappaB activation, P. carinii beta-glucan and LPS also utilize different receptor systems to induce macrophage activation. Macrophages from Toll-like receptor 4-deficient and wild type mice produced equivalent amounts of tumor necrosis factor alpha when stimulated with P. carinii beta-glucan. However, Toll-like receptor 4-deficient macrophages were refractory to stimulation with LPS. In contrast, MyD88-deficient macrophages exhibited a significant (though partial) blunted response to P. carinii beta-glucan. These data demonstrate that P. carinii beta-glucan acts as potent inducer of macrophage activation through NF-kappaB utilizing cellular receptors and signaling pathways distinct from LPS.

Animals↗
PubMed2004

TH1 immune responses to fully MHC mismatched allografts are diminished in the absence of MyD88, a toll-like receptor signal adaptor protein.

Toll-like receptors (TLRs) are innate immune receptors that are critical for recognizing conserved microbial motifs by inducing TH1 immunity. The majority of TLRs utilize the adaptor protein MyD88 for signal transduction, although other adaptors have been recently described. As the role of innate immunity in transplantation is unclear, we examined the importance of the MyD88 pathway in acute rejection of fully MHC-mismatched murine allografts and specifically investigated whether MyD88 signaling is important for DC (dendritic cell) function and TH1 alloimmune responses. Our results demonstrate that acute rejection of both fully allogeneic skin and cardiac allografts occurs in the absence of MyD88. However, priming of naïve recipient T cells by allogeneic DCs and TH1 immune responses were diminished in the absence of MyD88, although TH2 immunity remained intact. Thus, these results demonstrate that MyD88 signaling is important for DC function and TH1 responses during fully MHC-mismatched solid-organ transplantation, although graft rejection occurs independently of MyD88.

Adaptor Proteins, Signal Transducing↗
PubMed2006

[Aspergillus fumigatus activate human corneal epithelial cells via Toll-like receptor 2 and 4].

OBJECTIVE: To determine Toll-like receptors (TLR) 2 and TLR4 expression in human corneal epithelial tissue and cell line (THCE), and its activation by aspergillus fumigatus (AF) in inflammatory response. METHODS: The expression of TLR2 and TLR4 protein in human corneal epithelial tissue and THCE was detected by Western blot and immunocytochemistry. THCE was challenged with AF mycelium fragment (5 x 10(6)/ml) and supernatant extract agent (equivalent to bovine serum albumin 10 microg/ml). IL-8 and TNF-alpha in THCE supernatant were detected by ELISA at 1, 2, 4 and 8 h post stimulation. The protein of IkappaBalpha in THCE cells was assayed by Western blot at 30 min, 1 h and 2 h after treatment. Antibody blocking test was utilized to evaluate the effect on IL-8 and TNF-alpha expression of THCE by blocking TLR2 and (or) TLR4 before challenge with AF agent. RESULTS: TLR2 and TLR4 protein were expressed in human corneal epithelial tissue and THCE. The IL-8 and TNF-alpha level in THCE supernatant was elevated at 1 h, increased to (64.71 +/- 5.15) pg/ml and (32.46 +/- 3.28) pg/ml (AF mycelium challenge group), (94.94 +/- 11.92) pg/ml and (48.70 +/- 3.32) pg/ml (AF supernatant challenge group) 8 h post-challenged, which was 3.0 times and 2.5 times, 4.5 times and 3.5 times to that of control group respectively (P < 0.01). The activity of IkappaBalpha in THCE cells was decreased to 10.31 +/- 1.30 (gray scale value) and 8.15 +/- 2.37 at 30 min after challenged with AF mycelium or supernatant extract agent compared to 51.57 +/- 5.58 and 49.23 +/- 3.49 of control group (P < 0.01), and was reverted at 2 h. The secretion of IL-8 and TNF-alpha was partly inhibited by blocking TLR2 or TLR4 (P < 0.05), obviously inhibited by blocking TLR2 and TLR4 (50% and 40% compared to that of control group) (P < 0.01) when challenged with AF mycelium. And that was markedly inhibited by blocking TLR4 or blocking TLR2 and TLR4 when challenged with AF supernatant (P < 0.01). The secretion of IL-8 and TNF-alpha was not inhibited by blocking TLR2 when challenged with AF supernatant (P > 0.05). CONCLUSIONS: AF agent may induce human corneal epithelial cells express inflammatory cytokines via TLR-NF-kappaB pathway. TLR2 and TLR4 possibly mediate the recognition to AF mycelium, and TLR4 may dominate the recognition to AF supernatant agent.

Aspergillus fumigatus↗
PubMed2002

Toll-like receptor 9 mediates CpG-DNA signaling.

Among the bacterial products known to activate the innate immune '1system is bacterial DNA. This activity resides within the nonmethylated CpG motifs of the DNA and is recapitulated using appropriate synthetic CpG containing oligodeoxynucleotides (CpG-ODN). TLR9-deficient mice were shown to exhibit a nonresponsive phenotype-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 murine 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 containing an ectopically expressed TLR9 and endogenous receptor were compared. Here, we also show that TLR9 acts at the cell surface and engages an intracellular signaling pathway that includes MyD88, IRAK, and TRAF6.

Adaptor Proteins, Signal Transducing↗
PubMed2004

[Regulation of cytokine and toll-like receptor signaling by SOCS family genes].

Bacterial lipopolysaccharide (LPS) triggers innate immune responses through the Toll-like receptor (TLR) 4. Regulation of TLR signaling is a key step for inflammation, septic shock and innate/adaptive immunity. TLR signaling is shown to be regulated by cytokines, such as interferon-gamma (positive) and interleukin-10 and IL-4 (negative). However, molecular mechanisms of the regulation of LPS signaling by cytokines have not been clarified. Cytokine signaling is regulated by CIS/SOCS family proteins. Both SOCS1 and SOCS3 can inhibit JAK tyrosine kinase activity. We demonstrate that SOCS1 and SOCS3 play an important regulatory role in macrophages and dendritic cells (DCs) by modulating TLR signaling. SOCS1 negatively regulates not only the JAK/STAT pathway, but also the TLR-NF-kappaB pathway. SOCS3 protein was strongly induced by both IL-6 and IL-10 in the presence of LPS, but selectively inhibited IL-6 signaling. Therefore lack of SOCS3 gene in macrophages resulted in suppression of TLR signaling by hyperactivation of STAT3.

Animals↗
PubMed2002

The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors.

Mammalian Toll-like receptors (TLRs) function as sensors of infection and induce the activation of innate and adaptive immune responses. Upon recognizing conserved pathogen-associated molecular products, TLRs activate host defence responses through their intracellular signalling domain, the Toll/interleukin-1 receptor (TIR) domain, and the downstream adaptor protein MyD88 (refs 1-3). Although members of the TLR and the interleukin-1 (IL-1) receptor families all signal through MyD88, the signalling pathways induced by individual receptors differ. TIRAP, an adaptor protein in the TLR signalling pathway, has been identified and shown to function downstream of TLR4 (refs 4, 5). Here we report the generation of mice deficient in the Tirap gene. TIRAP-deficient mice respond normally to the TLR5, TLR7 and TLR9 ligands, as well as to IL-1 and IL-18, but have defects in cytokine production and in activation of the nuclear factor NF-kappaB and mitogen-activated protein kinases in response to lipopolysaccharide, a ligand for TLR4. In addition, TIRAP-deficient mice are also impaired in their responses to ligands for TLR2, TLR1 and TLR6. Thus, TIRAP is differentially involved in signalling by members of the TLR family and may account for specificity in the downstream signalling of individual TLRs.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Deficient tumor necrosis factor-alpha production in lipoarabinomannan activated macrophages from toll-like receptor-4 deficient mice: implication for mycobacterial susceptibility.

Mice with a point mutation of toll-like receptor-4 (TLR-4) (C3H/HeJ) are hypo-responsive to LPS and more susceptible to mycobacterial infections than their control wild type (C3H/OuJ). We have previously shown that TLR-4-deficient mice produced NO in response to the mycobacterial product, ara-lipoarabinomannan (LAM), in the presence of either Interferon-beta (IFN-beta) or Interferon-gamma (IFN-gamma), with a dose response curve that produced levels of NO almost as high as those observed in C3H/OuJ mice at high concentrations of ara-LAM plus either IFN-beta or-gamma. We now report that tumor necrosis factor-alpha (TNF-alpha), an important cytokine for intracellular killing of mycobacteria, remains deficient in these C3H/HeJ mice compared to C3H/OuJ mice even at a high concentration of ara-LAM with either IFN-gamma or IFN-beta. In addition, TNF-alpha was further down regulated by taurine chloramine (Tau-Cl) in C3H/OuJ mice. The low level of TNF-alpha produced in the TLR-4-deficient (C3H/HeJ) mice was also further down regulated by Tau-Cl. These findings implicate the TLR-4 as an additional candidate locus for mycobacterial susceptibility, and provide a pathway for better understanding the molecular basis of this locus in the immunopathogenesis of mycobacterial infection.

Animals↗
PubMed2004

Rac1 and Toll-IL-1 receptor domain-containing adapter protein mediate Toll-like receptor 4 induction of HIV-long terminal repeat.

Opportunistic infections, common in HIV-1-infected patients, increase HIV replication; however, the intracellular signaling mechanisms involved are not clearly known. We have shown that Toll-like receptor 2 (TLR2), TLR4, and TLR9 mediate microbial Ag-induced HIV-long terminal repeat (HIV-LTR) trans-activation and HIV-1 replication, and that LPS-induced HIV-LTR trans-activation is mediated through myeloid differentiation adapter protein. Recently, Toll-IL-1R domain-containing adapter protein (TIRAP) has been identified as an adapter molecule that mediates responses to TLR2 and TLR4 ligands, and TIRAP was suggested to provide signaling specificity for different TLRs. Rac1, a small GTP-binding protein that is activated upon LPS stimulation of macrophages, activates phosphatidylinositol 3-kinase and Akt and leads to NF-kappaB activation. The roles of Rac1 and TIRAP in LPS activation of HIV replication is not known. In the present study we show that LPS stimulation of human microvessel endothelial cells leads to Rac1 activation. Constitutively active Rac1 (Rac1V12) simulated the effect of LPS to activate HIV-LTR, whereas the expression of dominant negative Rac1 (Rac1N17) partially blocked LPS-induced HIV-LTR trans-activation. Rac1V12-induced HIV-LTR activation was independent of myeloid differentiation adapter protein, and dominant negative TIRAP blocked Rac1V12-induced HIV-LTR trans-activation. In this study we show for the first time that activation of Rac1 leads to HIV-LTR trans-activation, and this is mediated through TIRAP. Together these results underscore the importance of Rac1 and TIRAP in TLR4 activation of HIV replication and help delineate the signaling pathways induced by TLRs to mediate microbial Ag-induced HIV replication and HIV pathogenesis.

Cells, Cultured↗
PubMed2003

Francisella tularensis inhibits Toll-like receptor-mediated activation of intracellular signalling and secretion of TNF-alpha and IL-1 from murine macrophages.

Microbial ligands, including lipopolysaccharide (LPS) and bacterial lipoproteins, activate Toll-like receptors (TLR) of mononuclear phagocytes, thereby inducing proinflammatory cytokines and antimicrobial activity. We show that Francisella tularensis, an intracellular pathogen, is capable of inhibiting this macrophage response. Infection with the live vaccine strain F. tularensis LVS rendered cells of the murine macrophage-like cell line J774A.1 incapable of secreting TNF-alpha or IL-1beta and mobilizing an antimicrobial activity in response to bacterial lipopeptide or Escherichia coli-derived LPS. Inhibition of TNF-alpha secretion occurred also when J774 cells were infected with F. tularensis LVS in the presence of chloramphenicol, but not when they were infected with a mutant of F. tularensis LVS defective in expression of a 23 kDa protein that is upregulated during intracellular infection. Purified F. tularensis LPS did not show an agonistic or antagonistic effect on the E. coli LPS-induced activation of the J774 cells. Francisella tularensis LVS suppressed the capability of the cells to respond to LPS or bacterial lipopeptide (BLP) with activation of nuclear factor kappa B (NF-kappaB), and degradation of the in-hibitor of NF-kappaB, IkappaB, was blocked during the infection. Also the LPS- or BLP-induced phosphorylation of the mitogen-activated protein kinase p38 and the transcription factor c-Jun was inhibited by F. tularensis LVS but not by the 23 kDa protein mutant. In conclusion, F. tularensis appears capable of abrogating the TNF-alpha and IL-1 responses of macrophages induced by E. coli LPS or BLP via a mechanism that involves suppression of several intracellular pathways and is dependent on expression of a bacterial 23 kDa protein.

Animals↗
PubMed2003

Expression and function of Toll-like receptors 2 and 4 in human keratinocytes.

Keratinocytes have the ability to kill pathogenic fungi and bacteria by producing antimicrobial substances. Recent studies suggest that microbial components use signaling molecules of the human Toll-like receptor (TLR) family to transduce signals in various cells. Here we provide evidence that keratinocytes express both TLR2 and TLR4 at the mRNA and protein levels, and show that TLR2 and TLR4 are present in the normal human epidermis in vivo and that their expression is regulated by microbial components. The expression of myeloid differentiation protein gene (MyD88), which is involved in the signaling pathway of many TLR, was also demonstrated in keratinocytes. LPS + IFN-gamma increased the expression of TLR2 and TLR4 50- and 5-fold respectively. Treatment of keratinocytes with Candida albicans, mannan, Mycobacterium tuberculosis or LPS with IFN-gamma resulted in the activation and nuclear translocation of NF-kappaB. Inhibition of NF-kappaB blocked the Candida-killing activity of keratinocytes, suggesting that the antimicrobial effect of keratinocytes requires NF-kappaB activation. LPS + IFN-gamma, C. albicans (4 Candida/KC), peptidoglycan (1 micro g/ml) or M. tuberculosis extract significantly increased IL-8 gene expression after 3 h of treatment (P < 0.05). The increases over the 0-h level were 15-, 8-, 10.8- and 7-fold, respectively. The microbial compound-induced increase in IL-8 gene expression could be inhibited by anti-TLR2 and anti-TLR4 neutralizing antibodies, suggesting that TLRs are involved in the pathogen-induced expression of this pro-inflammatory cytokine. Our findings stress the importance of the role of keratinocytes as a component of innate immunity.

Adaptor Proteins, Signal Transducing↗
PubMed2006

TLR signaling.

The Toll-like receptor (TLR) family plays an instructive role in innate immune responses against microbial pathogens, as well as the subsequent induction of adaptive immune responses. TLRs recognize specific molecular patterns found in a broad range of microbial pathogens such as bacteria and viruses, triggering inflammatory and antiviral responses and dendritic cell maturation, which result in the eradication of invading pathogens. Individual TLRs interact with different combinations of adapter proteins and activate various transcription factors such as nuclear factor (NF)-kappaB, activating protein-1 and interferon regulatory factors, driving a specific immune response. This review outlines the recent advances in our understanding of TLR-signaling pathways and their roles in immune responses. Further, we also discuss a new concept of TLR-independent mechanisms for recognition of microbial pathogens.

Adaptor Proteins, Signal Transducing↗
PubMed2005

TLR7 ligand prevents allergen-induced airway hyperresponsiveness and eosinophilia in allergic asthma by a MYD88-dependent and MK2-independent pathway.

Asthma is one of the leading causes of childhood hospitalization, and its incidence is on the rise throughout the world. Currently, the standard treatment for asthma is the use of corticosteroids to try to suppress the inflammatory reaction taking place in the bronchial tree. Using a murine model of atopic allergic asthma employing a methacholine-hyperresponsive (A/J) as well as a hyporesponsive (C57BL/6) strain of mice sensitized and challenged with ovalbumin, we show that treatment with a synthetic Toll-like receptor 7 (TLR7) ligand (S-28463, a member of the imidazoquinoline family) prevents development of the asthmatic phenotype. Treatment with S-28463 resulted in a reduction of airway resistance and elastance following ovalbumin sensitization and challenge. This was accompanied by a dramatic reduction in infiltration of leukocytes, especially eosinophils, into the lungs of both C57BL/6 and A/J mice following OVA challenge. Treatment with S-28463 also abolished both the elevation in serum IgE level as well as the induction of IL-4, IL-5, and IL-13 by OVA challenge. The protective effects of S-28463 were also observed in MK2 knockout, but not MYD88 knockout, mice. We did not observe a switch in cytokine profile from T(H)2 to T(H)1, as both IL-12p70 and IFN-gamma levels were reduced following S-28463 treatment. These results clearly demonstrate the anti-inflammatory effect of imidazoquinolines in an allergic asthma model as well as the clinical potential of TLR7 ligands in the treatment of allergic diseases.

Adaptor Proteins, Signal Transducing↗