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PubMed2006

Toll-like receptor 9-mediated induction of the immunosuppressive pathway of tryptophan catabolism.

A series of recent studies, including an article in this issue of the European Journal of Immunology, have demonstrated that the administration of CpG-rich oligodeoxynucleotides (CpG-ODN) in experimental settings may lead to the activation of the immunosuppressive pathway of tryptophan catabolism, depending on several factors, including the route of CpG-ODN administration. These studies call attention to the need for a careful evaluation of the modalities of inclusion of CpG-ODN in vaccines for human use. At the same time, these studies may offer novel opportunities for use of CpG-ODN as immunosuppressive agents and may also lead to an improved understanding of the cellular events mediated by Toll-like receptor 9 signaling.

Adjuvants, Immunologic↗
PubMed2003

Heat-killed Brucella abortus induces TNF and IL-12p40 by distinct MyD88-dependent pathways: TNF, unlike IL-12p40 secretion, is Toll-like receptor 2 dependent.

Cattle and humans are susceptible to infection with the Gram-negative intracellular bacterium Brucella abortus. Heat-killed B. abortus (HKBA) is a strong Th1 adjuvant and carrier. Previously, we have demonstrated that dendritic cells produce IL-12 in response to HKBA stimulation. In the present study, we use knockout mice and in vitro reconstitution assays to examine the contribution of signaling by Toll-like receptors (TLRs) and their immediate downstream signaling initiator, myeloid differentiation protein MyD88, in the activation following stimulation by HKBA. Our results show that HKBA-mediated induction of IL-12p40 and TNF is dependent on the adapter molecule MyD88. To identify the TLR involved in HKBA recognition, we examined HKBA responses in TLR2- and TLR4-deficient animals. TNF responses to HKBA were TLR4 independent; however, the response in TLR2-deficient mice was significantly delayed and reduced, although not completely abolished. Studies using Chinese hamster ovary/CD14 reporter cell lines stably transfected with either human TLR2 or human TLR4 confirmed the results seen with knockout mice, namely TLR2, but not TLR4, can mediate cellular activation by HKBA. In addition, human embryonic kidney 293 cells, which do not respond to HKBA, were made responsive by transfecting TLR2, but not TLR4 or TLR9. Taken together, our data demonstrate that MyD88-dependent pathways are crucial for activation by HKBA and that TLR2 plays a role in TNF, but not IL-12p40 pathways activated by this microbial product.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Innate immunity: sensing the environment and regulating the regulators.

PURPOSE OF REVIEW: Innate immune cells act as sensors for environmental pathogens and key regulators of pathogen-specific T-cell effector responses. The expression of Toll-like receptors is essential for these functions. Innate immunity is a rapidly evolving field. Great progress has been made in the past year in characterizing the signaling pathways downstream of Toll-like receptors, and the role of Toll-like receptors in the regulation of pathogen responses. RECENT FINDINGS: The ability to control the activation of regulatory T cells has emerged as a key function of innate immunity. Regulatory T cells are involved in the induction of tolerance and the prevention of harmful immune pathology, particularly T-cell responses directed against self-antigens. Toll-like receptor-mediated interactions between pathogen-stimulated innate immune cells and regulatory T cells result in the release of suppression by regulatory T cells, thus allowing pathogen-specific responses. However, pathogenic microorganisms may exploit this interaction to evade the host's response. In addition, recent studies raise the possibility that regulatory T cells may express some Toll-like receptor family members, thereby responding directly to pathogens. SUMMARY: A deeper understanding of the complex role of innate immune cells as sensors of the environment and regulators of pathogen responses will probably influence the current models of immune regulation, particularly those centered on the role of the environment in shaping immune responses.

CD4-Positive T-Lymphocytes↗
PubMed2006

Toll-like receptor recognition of Toxoplasma gondii.

Toxoplasma gondii potently stimulates IFN-gamma production by both the innate and adaptive immune system as part of its host adaptation. This response is known to be dependent on an Myeloid Differentiation factor 88 signaling pathway used by Toll-like receptors (TLRs), a family of proteins involved in the recognition of microbial molecular patterns. In the following review, we summarise the evidence for specific TLR function in host resistance to T. gondii focusing on the recent discovery in the parasite of a profilin-like ligand that potently stimulates TLR11 and regulates the production of IL-12, a cytokine necessary for the protective IFN-gamma response. In addition, we discuss the hypothesis that TLR11 may have evolved as a general pattern recognition receptor for apicomplexan protozoa and that as highly conserved proteins associated with actin-based motility, profilins are logical ligand targets for this form of pathogen detection. Finally, we review the evidence for involvement of other TLR and TLR ligands in host resistance to T. gondii and discuss how such receptors might synergise with TLR11 in the innate response to the parasite.

Animals↗
PubMed2005

[On mechanism of how lipopolysaccharide induces dendritic cells to mature through TLRs signal pathway].

OBJECTIVE: To find out how lipopolysaccharide (LPS) induces dendritic cells (DC) to be more mature through Toll-like receptors (TLRs) signal pathway. METHODS: Monocytes were isolated from heparinized whole blood. 7 days later the monocytes were induced into dendritic cells by adding rhGM-CSF and rhIL-4. Total cellular RNA of unstimulated and stimulated DC were extracted by LPS 24 h later. Semi-quantitative RT-PCR and agarose gel electrophoresis were conducted to analyze the PCR products. The expression of NF-kappaB was detected by laser scanning confocal microscopy (LSCM). RESULTS: Expressions of TLR2, 3, 4 were significantly higher in monocytes-derived DC induced for 7 days, the plasm of DC was stained positive and the nucleus of DC was stained negative. After being stimulated by LPS for 24 h, the expressions of TLR2, 3, 4 decreased, and that of TLR4 was almost undetectable; the nucleus of DC was stained strong positive, the plasm of DC was stained positive. CONCLUSION: The expressions of TLR2, 3, 4 on DC change significantly after being stimulated by LPS. And NF-kappaB shifts from the plasm to the nucleus. This signifies that LPS induces DC to be more mature in function.

Adolescent↗
PubMed2001

A family of proteins related to Spätzle, the toll receptor ligand, are encoded in the Drosophila genome.

The Drosophila gene Spätzle encodes the activating ligand for the Toll receptor. This signaling pathway is required for dorso-ventral patterning in the early embryo and an antifungal immune response in larvae and adults. The genome sequence of Drosophila shows that there are a total of eight Toll-like receptors and these may function in other aspects of embryonic development and innate immunity. Here we describe five Drosophila homologues of Spätzle (Spz2-6) found using an iterative searching method. All five appear to encode proteins containing neurotrophin-like cystine-knot domains. In addition, most retain a characteristic intron-exon structure shared with the prototype Spätzle gene. This provides evidence that the family arose by ancient gene duplication events and indicates that the gene products may represent activating ligands for corresponding Toll receptors. Expression studies show that only Spz4 is expressed strongly in larvae and adults and thus may be involved in an ancillary antifungal response mediated by Toll-5. By contrast, Spz6 shows a complex spatial and temporally regulated expression pattern in the late embryo. Thus the new Toll/Spätzle families of signaling molecules may have important roles in other aspects of development and immunity.

Amino Acid Sequence↗
PubMed2005

Mucosal epithelium in health and disease.

The intestinal epithelium has emerged as one of the links between the innate and adaptive immune systems. Novel roles have been elucidated for its participation in antigen uptake and presentation, costimulatory signaling, and intestinal homeostasis. Its concomitant interaction with immune cells and commensal flora demonstrates the epithelium's multifaceted responsibility in protecting against intestinal pathology while maintaining immune competence. Its functional capacity is now more clearly defined in disease states such as celiac disease, Crohn's disease, and ulcerative colitis and in maintaining intestinal integrity through toll-like receptor signaling pathways.

Antigen Presentation↗
PubMed2004

Thymosin alpha 1 activates dendritic cells for antifungal Th1 resistance through toll-like receptor signaling.

Dendritic cells (DCs) show a remarkable functional plasticity in the recognition of Aspergillus fumigatus and orchestrate the antifungal immune resistance in the lungs. Here, we show that thymosin alpha 1, a naturally occurring thymic peptide, induces functional maturation and interleukin-12 production by fungus-pulsed DCs through the p38 mitogen-activated protein kinase/nuclear factor (NF)-kappaB-dependent pathway. This occurs by signaling through the myeloid differentiation factor 88-dependent pathway, involving distinct Toll-like receptors. In vivo, the synthetic peptide activates T-helper (Th) cell 1-dependent antifungal immunity, accelerates myeloid cell recovery, and protects highly susceptible mice that received hematopoietic transplants from aspergillosis. By revealing the unexpected activity of an old molecule, our finding provides the rationale for its therapeutic utility and qualify the synthetic peptide as a candidate adjuvant promoting the coordinated activation of the innate and adaptive Th immunity to the fungus.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Rel homology domain-containing transcription factors in the cnidarian Nematostella vectensis.

The Rel/NF-kappaB and NFAT families of transcription factors are related through an N-terminal DNA-binding domain called the Rel Homology domain (RHD). Neither the RHD nor the NF-kappaB pathway has been identified in a basal (i.e., nonbilaterian) animal phylum. Using genomic and cDNA databases, we have identified two RHD domain-containing proteins from the cnidarian Nematostella vectensis: an NF-kappaB-like protein (Nv-NF-kappaB) and an NFAT-like protein (Nv-NFAT). The gene structure and RHD predicted amino acid sequence of Nv-nfkb are similar to those of the vertebrate NF-kappaB p50/p52 proteins, whereas the sequence of Nv-NFAT allows only ambiguous assignment to the NFAT family. Nv-NF-kappaB lacks the C-terminal IkappaB-like sequences present in all other NF-kappaB proteins. There are, however, two IkappaB-like genes in Nematostella encoded by loci distinct from Nv-nfkb. The separate nfkb and ikb genes of Nematostella may reflect the ancestral metazoan condition, suggesting that a gene fusion event created the nfkb genes in Drosophila and vertebrates. Nematostella also has genes that encode upstream and downstream components of the vertebrate NF-kappaB signaling pathway. Upstream components include Toll- and tumor necrosis-like receptors and ligands, adaptor proteins (Trafs, Myd88), caspases, and a TBK-like kinase. Downstream components include the NF-kappaB coactivator protein Bcl-3 and several NF-kappaB target genes. These results demonstrate that RHD-containing transcription factors and associated pathways are evolutionarily more ancient than previously known. Moreover, they suggest models for the evolutionary diversification of the insect and vertebrate Rel/NF-kappaB/IkappaB and NFAT gene families and suggest that cnidarians possess an NF-kappaB-regulated developmental or stress response pathway.

Amino Acid Sequence↗
PubMed2003

Crosstalk between LXR and toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism.

The liver X receptors (LXR) alpha and beta are regulators of cholesterol metabolism and determinants of atherosclerosis susceptibility. Viral and bacterial pathogens have long been suspected to be modulators of atherogenesis; however, mechanisms linking innate immunity to cholesterol metabolism are poorly defined. We demonstrate here that pathogens interfere with macrophage cholesterol metabolism through inhibition of the LXR signaling pathway. Activation of Toll-like receptors (TLR) 3 and 4 by microbial ligands blocks the induction of LXR target genes including ABCA1 in cultured macrophages as well as in aortic tissue in vivo. As a consequence of these transcriptional effects, TLR3/4 ligands strongly inhibit cholesterol efflux from macrophages. Crosstalk between LXR and TLR signaling is mediated by IRF3, a specific effector of TLR3/4 that inhibits the transcriptional activity of LXR on its target promoters. These findings highlight a common mechanism whereby bacterial and viral pathogens may modulate macrophage cholesterol metabolism and cardiovascular disease.

ATP Binding Cassette Transporter 1↗
PubMed2026

Liver transcriptome analysis revealed multiple immune processes and lipid metabolism pathways involved in the defense response of the turbot (Scophthalmus maximus) against Aeromonas salmonicida.

Aeromonas salmonicida is a significant pathogen causing notable economic losses in Scophthalmus maximus aquaculture. This study utilized Illumina sequencing technology to examine the transcriptional response characteristics of S. maximus liver at 24 h following A. salmonicida infection. A total of 2363 differentially expressed genes (DEGs) were identified when compared to the negative control group. The immunity-related Toll-like receptor signaling pathway, NOD-like receptor signaling pathway, as well as metabolism-related PPAR signaling pathway and insulin signaling pathway, were notably enriched. Significant differences exist in the expression of key genes within the PPAR pathway, particularly cd36, acsl4a, pparαa, and plin2, all of which mediate the interaction between lipid metabolism and the immune response. These results offer valuable insights into the immunometabolic regulatory mechanism of S. maximus response to A. salmonicida infection.

Animals↗
PubMed2002

Cell activation by Porphyromonas gingivalis lipid A molecule through Toll-like receptor 4- and myeloid differentiation factor 88-dependent signaling pathway.

Porphyromonas gingivalis lipopolysaccharide (LPS) and its bioactive center, lipid A, are known to exhibit very low endotoxic activities and activate LPS-hyporesponsive C3H/HeJ mice that have a point mutation in the cytoplasmic portion of Toll-like receptor (TLR) 4, in contrast to classical enterobacterial LPS and their lipid A. In the present study, we attempted to determine which TLR mediates the response to lipid A from P. gingivalis strain 381. P. gingivalis LPS and its natural lipid A fraction induced NF-kappa B activation primarily in Ba/F3 cells expressing mouse TLR 2 (Ba/mTLR2), rather than in those expressing mouse TLR4 and its accessory protein MD2 (Ba/mTLR4/mMD2). Further purification of the natural lipid A fraction resulted in a significant decrease of NF-kappa B activation in Ba/mTLR2, although not in Ba/mTLR4/mMD2. The synthetic counterpart of P. gingivalis strain 381-lipid A (compound PG-381) also elicited NF-kappa B activation in Ba/mTLR4/mMD2, but not Ba/mTLR2. Furthermore, P. gingivalis purified natural lipid A and compound PG-381 lacked the ability to activate gingival fibroblasts from C3H/HeJ, TLR4 knockout (KO) and myeloid differentiation factor 88 (MyD88) KO mice. These findings demonstrate that the P. gingivalis lipid A molecule induces cell activation via a TLR4/MD2-MyD88-dependent pathway, and suggest the possibility that unknown bacterial components in P. gingivalis LPS and its lipid A may induce cell activation via TLR2.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Gene expression profiling of avian macrophage activation.

Through the process of phagocytosis, the macrophage is responsible for the clearance and destruction of both intracellular and extracellular pathogens. When stimulated, macrophages undergo a process of activation involving an increase in size and motility, enhanced phagocytic, bactericidal, and tumoricidal activity, and up-regulation of several cell-surface markers. One well characterized method of mammalian macrophage activation involves the Toll-like receptor (TLR) pathway. TLRs are surface molecules that function as direct receptors for microbial components. Binding of ligand to TLRs results in activation of transcription factors that regulate genes involved in microbial killing, apoptosis, and antigen recognition, as well as pro- and anti-inflammatory cytokines and chemokines. We have constructed a 4906-element (14,718 spot) avian macrophage-specific cDNA microarray (AMM). The AMM contains 16 of the approximately 44 genes identified within the mammalian TLR pathway. This array was used to examine the transcriptional response of avian macrophages to Gram-negative bacteria and their cell wall components and to evaluate the contribution of the avian TLR pathway to that response. Of the elements on the AMM, 981 (20%) exhibited significant (greater than two-fold, p < 0.01) changes in expression during phagocytosis of Escherichia coli and 243 (5%) exhibited significant expression changes during exposure to lipopolysaccharide (LPS). A unique set of overlapping elements (154), were observed to exhibit significant changes in expression for both phagocytosis and LPS stimulation, representing a set of core response elements. Of these elements, 63% were commonly induced, while 32% were commonly repressed. Both LPS and bacteria were found to induce NFkappabeta and several end products of the TLR pathway.

Animals↗
PubMed2003

Role of nod2 in the response of macrophages to toll-like receptor agonists.

Nod2 (CARD15) is a macrophage-specific protein containing two CARD domains, a large nucleotide binding domain and leucine-rich repeats. Human genetic studies have linked mutations in NOD2/CARD15 with Crohn's disease, although the mechanisms involved are unknown. However, Nod2 has been proposed to directly bind bacterial lipopolysaccharide (LPS) and subsequently act as an activator of NF-kappaB via the association of the CARD domains with Rip2/RICK/CARDIAK. This is hypothesized to constitute a pathogen recognition pathway distinct from Toll-like receptor 4-mediated recognition of LPS. Using targeted mutagenesis, we introduced a mutation to delete the CARD domains of mouse Nod2. Mice lacking Nod2 were indistinguishable from controls and showed no signs of intestinal pathology. Macrophages responded normally to multiple Toll-like receptor agonists in terms of NF-kappaB target activation, mitogen-activated protein kinase activation, and cytokine secretion. However, Nod2(-/-) mice were significantly protected in endotoxin challenge experiments, and Nod2(-/-) macrophages were refractory to muramyl dipeptide stimulation. These results argue that Nod2 does not play an essential, nonredundant role in the response of macrophages to bacterial products but rather plays unexpected roles in regulating systemic responses to pathogens.

Amino Acid Sequence↗
PubMed2004

Involvement of CD14 and toll-like receptor 4 in the acute phase response of serum amyloid A proteins and serum amyloid P component in the liver after burn injury.

Acute phase proteins such as serum amyloid A proteins (SAAs) and serum amyloid P component (SAP) are induced in the liver after various insults (e.g., infection, injury). The cellular and molecular mechanisms controlling the expression of these acute phase proteins may be specifically designed for different insults. The roles of two central molecules of the lipopolysaccharide (LPS)-mediated inflammation pathway (CD14 and toll-like receptor 4 [Tlr4]) were investigated for the regulation of SAAs and SAP in the liver of mice after an 18% total body surface area burn injury. RT-PCR analysis revealed a subtype- and time-dependent induction of SAA mRNAs between 3 h and 3 days, while there was a peak induction of SAP mRNA at day 1. Marked elevations of SAA and SAP protein levels at day 1 supported the mRNA data. Furthermore, a differential regulation of SAAs and SAP mRNAs was noted between CD14 knockout (KO) and their control mice after injury. SAA protein was induced to a lesser degree after injury in C3H/HeJ (Tlr4-defective) mice than in their control mice. In addition, in both CD14 KO and C3H/HeJ mice, the induction of SAP protein was significantly reduced compared with respective controls. These data provide evidence that CD14 and Tlr4 participate, at least in part, in a cascade of signaling events that control the immediate-early and differential induction of SAAs and SAP in the liver after injury. They also suggest that LPS may be one of the initial inducing agents associated with these acute phase responses in the liver after injury.

Acute-Phase Reaction↗
PubMed2002

Induction of keratinocyte growth factor 1 Expression by lipopolysaccharide is regulated by CD-14 and toll-like receptors 2 and 4.

Periodontal disease is a chronic inflammatory condition that is associated with increased concentrations of gram-negative pathogenic bacteria and epithelial cell proliferation. Regulation of this proliferation is poorly understood but is most likely controlled by locally expressed growth factors. Keratinocyte growth factor 1, an epithelium-specific growth factor, is expressed by gingival fibroblasts, and its expression is regulated in a concentration-dependent manner by lipopolysaccharide. In this study, induction of keratinocyte growth factor 1 protein expression was dependent on gingival fibroblast expression of membrane CD14 (mCD14) and Toll-like receptors 2 and 4. Lipopolysaccharides from Escherichia coli and Porphyromonas gingivalis induced membrane expression of CD14 at 1, 3, and 24 h. Specifically, lipopolysaccharide induced low mCD14 expression gingival fibroblasts to express mCD14 at a level consistent with that of high mCD14 expression cells. Functional studies with specific blocking antibodies for CD14 and Toll-like receptors 2 and 4 implicated all of these molecules in signal transduction. The rapid decrease in cell membrane expression of Toll-like receptors 2 and 4 after treatment with lipopolysaccharide was consistent with receptor internalization, and blocking of either of these receptors completely inhibited keratinocyte growth factor 1 protein expression. The transcription factors AP-1 and NF-kappaB were involved in lipopolysaccharide induction of keratinocyte growth factor 1 mRNA and protein expression. These results suggest that lipopolysaccharide may induce proliferation of periodontal epithelial cells by upregulating keratinocyte growth factor 1 expression via the CD14 and Toll-like receptor signaling pathway.

Cells, Cultured↗
PubMed2006

Activation of IFN pathways and plasmacytoid dendritic cell recruitment in target organs of primary Sjögren's syndrome.

Gene expression analysis of target organs might help provide new insights into the pathogenesis of autoimmune diseases. We used global gene expression profiling of minor salivary glands to identify patterns of gene expression in patients with primary Sjögren's syndrome (pSS), a common and prototypic systemic autoimmune disease. Gene expression analysis allowed for differentiating most patients with pSS from controls. The expression of 23 genes in the IFN pathways, including two Toll-like receptors (TLR8 and TLR9), was significantly different between patients and controls. Furthermore, the increased expression of IFN-inducible genes, BAFF and IFN-induced transmembrane protein 1, was also demonstrated in ocular epithelial cells by quantitative RT-PCR. In vitro activation showed that these genes were effectively modulated by IFNs in salivary gland epithelial cells, the target cells of autoimmunity in pSS. The activation of IFN pathways led us to investigate whether plasmacytoid dendritic cells were recruited in salivary glands. These IFN-producing cells were detected by immunohistochemistry in all patients with pSS, whereas none was observed in controls. In conclusion, our results support the pathogenic interaction between the innate and adaptive immune system in pSS. The persistence of the IFN signature might be related to a vicious circle, in which the environment interacts with genetic factors to drive the stimulation of salivary TLRs.

Adult↗
PubMed2005

The serine protease Sp7 is expressed in blood cells and regulates the melanization reaction in Drosophila.

Serine proteases play a central role in defense against pathogens by regulating processes such as blood clotting, melanization of injured surfaces, and proteolytic activation of signaling pathways involved in innate immunity. Here, we present the functional characterization of the Drosophila serine protease Sp7 (CG3006) by inducible RNA interference. We show that Sp7 is constitutively expressed in blood cells during embryonic and larval stages. Silencing of the gene impairs the melanization reaction upon injury. Our data demonstrate that Sp7 is required for phenoloxidase activation and its activity is restricted to a subclass of blood cells, the crystal cells. Transcriptional up-regulation of Sp7 was observed after clean, septic injury and in flies expressing an activated form of Toll; however, mutations in the Toll or the IMD pathway did not abolish expression of Sp7, indicating the existence of other regulatory pathways and/or independent basal transcription.

Animals↗