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PubMed2004

Endotoxin recognition and signal transduction by the TLR4/MD2-complex.

Bacterial lipopolysaccharides are recognized in mammals by a receptor complex composed of CD14, Toll-like receptor (TLR)-4 and MD-2. Transduction of signaling is achieved following the recruitment of a combination of four Toll-interleukin-1 resistance (TIR)-domain-containing adapter molecules, which provide a structural platform enabling the recruitment and activation of downstream effectors essential for pathway-specific transcription factor activation and inflammatory gene expression.

Animals↗
PubMed2006

Adenovirus RIDalphabeta complex inhibits lipopolysaccharide signaling without altering TLR4 cell surface expression.

The transmembrane heterotrimer complex 10.4K/14.5K, also known as RID (for "receptor internalization and degradation"), is encoded by the adenovirus E3 region, and it down-regulates the cell surface expression of several unrelated receptors. We recently showed that RID expression correlates with down-regulation of the cell surface expression of the tumor necrosis factor (TNF) receptor 1 in several human cells. This observation provided the first mechanistic explanation for the inhibition of TNF alpha-induced chemokines by RID. Here we analyze the immunoregulatory activities of RID on lipopolysaccharide (LPS) and interleukin-1 beta (IL-1beta)-mediated responses. Although both signaling pathways are strongly inhibited by RID, the chemokines up-regulated by IL-1beta stimulation are only marginally inhibited. In addition, RID inhibits signaling induced by LPS without affecting the expression of the LPS receptor Toll-like receptor 4, demonstrating that RID need not target degradation of the receptor to alter signal transduction. Taken together, our data demonstrate the inhibitory effect of RID on two additional cell surface receptor-mediated signaling pathways involved in inflammatory processes. The data suggest that RID has intracellular targets that impair signal transduction and chemokine expression without evidence of receptor down-regulation.

Adenovirus E3 Proteins↗
PubMed2000

OmpA targets dendritic cells, induces their maturation and delivers antigen into the MHC class I presentation pathway.

We analyzed the interaction between a bacterial cell wall protein and dendritic cells (DCs). Outer membrane protein A from Klebsiella pneumoniae (kpOmpA) specifically bound to professional antigen presenting cells and was endocytosed by immature DCs via a receptor-dependent mechanism. kpOmpA signaled through Toll-like receptor 2, induced DCs to produce interleukin 12 and induced maturation of DCs. Whole antigen that was coupled to kpOmpA and injected into mice was taken up by DCs and delivered to the conventional cytosolic MHC class I presentation pathway. kpOmpA also primed antigen-specific CD8+ CTLs in the absence of CD4+ T cell help or adjuvant and elicited therapeutic immunity to antigen-expressing tumors. Thus, OmpA belongs to a class of proteins that are able to elicit CTL responses to exogenous antigen.

Animals↗
PubMed2004

Ectopic expression of toll-like receptor-3 (TLR-3) overcomes the double-stranded RNA (dsRNA) signaling defects of P2.1 cells.

Cells respond to viral infection through induction of discrete, innate immune response pathways that lead to induction of interferons (IFNs) and other proinflammatory cytokines, as well as the direct induction of some IFN-responsive genes that mediate specific antiviral or immunomodulatory responses. To assess the classes of genes induced directly upon treatment of cells with double-stranded RNA (dsRNA), a mimic of viral infection, we made use of a mutant human cell line defective in responsiveness to dsRNA and IFN. P2.1 mutant cells were generated from a Jak1-minus, HT1080 fibrosarcoma-derived cell line (U4C) after extensive mutagenesis with the intercalating agent ICR191. We now demonstrate that P2.1 cells are defective in basal and induced expression of toll-like receptor-3 (TLR-3), which may contribute to their dsRNA-unresponsive phenotype. After transfection with a wild-type TLR-3 gene, P2.1 cells were largely responsive to a dsRNA challenge, as assessed by activation of NF-kappaB and IFN regulatory factors (IRFs) and induction of IFN-beta and other genes. Untransfected and TLR-3-transfected P2.1 cells were assessed for global dsRNA responsiveness in oligonucleotide gene array studies alongside parental U4C and HT1080 cells. Several distinct patterns of gene induction in response to dsRNA challenge were identified, including genes expressed in a TLR-3-dependent manner, genes that required an intact IFN feedback for expression, and dsRNA-responsive genes that appeared not to require TLR-3 for induction. These data support the hypothesis that TLR-3 is an important determinant of cellular responses to external dsRNA and demonstrate distinctions in the repertoires of dsRNA-regulated genes induced when the IFN-feedback loop is present or absent in cells.

Apoptosis↗
PubMed2001

Endotoxin-induced maturation of MyD88-deficient dendritic cells.

LPS, a major component of the cell wall of Gram-negative bacteria, can induce a variety of biological responses including cytokine production from macrophages, B cell proliferation, and endotoxin shock. All of them were completely abolished in MyD88-deficient mice, indicating the essential role of MyD88 in LPS signaling. However, MyD88-deficient cells still show activation of NF-kappaB and mitogen-activated protein kinase cascades, although the biological significance of this activation is not clear. In this study, we have examined the effects of LPS on dendritic cells (DCs) from wild-type and several mutant mice. LPS-induced cytokine production from DCs was dependent on MyD88. However, LPS could induce functional maturation of MyD88-deficient DCs, including up-regulation of costimulatory molecules and enhancement of APC activity. MyD88-deficient DCs could not mature in response to bacterial DNA, the ligand for Toll-like receptor (TLR)9, indicating that MyD88 is differentially required for TLR family signaling. MyD88-dependent and -independent pathways originate at the intracytoplasmic region of TLR4, because both cytokine induction and functional maturation were abolished in DCs from C3H/HeJ mice carrying the point mutation in the region. Finally, in vivo analysis revealed that MyD88-, but not TLR4-, deficient splenic CD11c(+) DCs could up-regulate their costimulatory molecule expression in response to LPS. Collectively, the present study provides the first evidence that the MyD88-independent pathway downstream of TLR4 can lead to functional DC maturation, which is critical for a link between innate and adaptive immunity.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Coupling Toll-like receptor signaling with phagocytosis: potentiation of antigen presentation.

Much attention has focused on the role of co-stimulation in dictating tolerance versus immunity to internalized antigens, with the assumption that the presentation of antigen-derived peptides by MHC molecules occurs constitutively. Here, I highlight our new appreciation for the regulated presentation of phagocytosed antigens by MHC class II molecules as a direct result of controlling phagosome maturation by Toll-like receptors. I discuss how the mode of antigen delivery into dendritic cells coupled with the right type of signal transduction pathway can impact greatly not only the co-stimulatory context in which the antigen is presented to naive T cells (signal 2) but MHC-II presentation of the antigen and formation of the T-cell receptor ligand (signal 1) itself.

Animals↗
PubMed2005

[Toll-like receptor].

Toll-like receptors (TLRs) have been revealed to recognize specific patterns of microbial components. Recognition of microbial components by TLRs initiates signal transduction pathways, triggering expression of genes, which products control innate immune responses and further instruct development of antigen-specific acquired immunity. TIR domain-containing adaptors, such as MyD88, TIRAP, TRIF, and TRAM, play pivotal roles in TLR signaling pathways. Differential utilization of these TIR domain-containing adaptors provides specificity of individual TLR-mediated signaling pathways. TLR-mediated activation of innate immunity, when in excess, leads to immune disorders such as inflammatory bowel diseases. Therefore, several mechanisms that negatively control TLR signaling pathways and thereby prevent overactivation of innate immunity have been elucidated. Nuclear IkappaB proteins, such as Bcl-3 and IkappaBNS, have been revealed to be responsible for this process, by differentially inhibiting TLR-dependent cytokine production.

Animals↗
PubMed2004

Does Toll-like receptor 3 play a biological role in virus infections?

The Toll-like receptor (TLR) family functions to recognize conserved microbial and viral structures with the purpose of activating signal pathways to instigate immune responses against infections by these organisms. For example, in vitro studies reveal that the TLR3 ligand is a double-stranded RNA (dsRNA), a product of viral infections. From this observation, it has been proposed that TLR3 is likely an important first signal for virus infections. We approached this issue by investigating the role of TLR3 in four different infectious viral models (lymphocytic choriomeningitis virus (LCMV), vesicular stomatitis virus (VSV), murine cytomegalovirus (MCMV), and reovirus) and in TLR3 genetically deficient ((-/-)) mice. Our results indicate that TLR3 is not universally required for the generation of effective antiviral responses because the absence of TLR3 does not alter either viral pathogenesis or impair host's generation of adaptive antiviral responses to these viruses.

Animals↗
PubMed2006

Apoptotic vesicles crossprime CD8 T cells and protect against tuberculosis.

CD8 T lymphocytes are important effectors in protective immunity against Mycobacterium tuberculosis. We recently characterized the detour pathway of CD8 T cell activation in tuberculosis mediated by apoptotic vesicles from infected cells that transport mycobacterial antigens to dendritic cells (DCs). Here we demonstrate that apoptotic vesicles from mycobacteria-infected macrophages stimulate CD8 T cells in vivo. Homing of DCs to draining lymph nodes was critically required for effective crosspriming. Subsequent fate of vesicle-associated antigens in recipient DCs was characterized by endosomal mechanisms predominating over proteasomal processing. In addition, vesicle processing depended on the presence of saposins to disintegrate apoptotic membranes. Apoptotic vesicles displayed potent adjuvant activity by stimulating through Toll-like receptors (TLR). Ultimately, vaccination with vesicles from infected cells induced protection against M. tuberculosis infection. Taken together, we propose the detour pathway to represent a genuine immunological mechanism mediating crosspriming of CD8 T cells in vivo and protection against tuberculosis.

Adjuvants, Immunologic↗
PubMed1999

A single growth cone is capable of integrating simultaneously presented and functionally distinct molecular cues during target recognition.

A variety of cell recognition pathways affect neuronal target recognition. However, whether such pathways can converge at the level of a single growth cone is not well known. The RP3 motoneuron in Drosophila has previously been shown to respond to the muscle cell surface molecules TOLL and fasciclin III (FAS3), which are normally encountered during RP3 pathfinding in a sequential manner. TOLL and FAS3, putative "negative" and "positive" recognition molecules, respectively, affect RP3 antagonistically. Under normal conditions, TOLL and FAS3 together improve the accuracy of its target recognition. Here, we show that, when presented with concurrent TOLL and FAS3 expression, RP3 responds to both, integrating their effects. This was demonstrated most succinctly by single cell visualization methods. When a balance in relative expression levels between the two antagonistic cues is achieved, the RP3 growth cone exhibits a phenotype virtually identical to that seen when neither TOLL nor FAS3 is misexpressed. Thus, growth cones are capable of quantitatively evaluating distinct recognition cues and integrating them to attain a net result, in effect responding to the "balance of power" between positive and negative influences. We suggest that the ability to integrate multiple recognition pathways in real-time is one important way in which an individual growth cone interprets and navigates complex molecular environments.

Animals↗
PubMed2003

Role of Toll-like receptor signaling in the apoptotic response of macrophages to Yersinia infection.

Macrophages encode several Toll-like receptors (TLRs) that recognize bacterial components, such as lipoproteins (TLR2) or lipopolysaccharides (TLR4), and activate multiple signaling pathways. Activation of transcription factor NF-kappaB by TLR2 or TLR4 signaling promotes proinflammatory and cell survival responses. Alternatively, TLR2 or TLR4 signaling can promote apoptosis if the activation of NF-kappaB is blocked. The gram-negative bacterial pathogen Yersinia pseudotuberculosis secretes into macrophages a protease (YopJ) that inhibits the activation of NF-kappaB and promotes apoptosis. We show that primary macrophages expressing constitutively active inhibitor kappaB kinase beta (IKKbeta) are completely resistant to YopJ-dependent apoptosis, indicating that YopJ inhibits signaling upstream of IKKbeta. Apoptosis is reduced two- to threefold in TLR4(-/-) macrophages infected with Y. pseudotuberculosis, while the apoptotic response of TLR2(-/-) macrophages to Y. pseudotuberculosis infection is equivalent to that of wild-type macrophages. Therefore, TLR4 is the primary source of apoptotic signaling in Yersinia-infected macrophages. Our results also show that a small percentage of macrophages can die as a result of an apoptotic process that is YopJ dependent but does not require TLR2 or TLR4 signaling.

3T3 Cells↗
PubMed2002

[Induction of direct antimicrobial activity through mammalian toll-like receptors].

Drosophila, the toll gene controls a powerful innate defense system against bacteria and fungi. Conserved through evolution, the mammalian innate immune system retains a family of homologous Toll-like receptors (TLRs) that are activated by microbial ligands to release cytokines that instruct the adaptive immune responses. Here we show that TLR2 activation leads to killing of intracellular Mycobacterium (M.) tuberculosis in both mouse and human macrophages. In mouse macrophages, bacterial lipoprotein activation of TLR2 leads to a nitric oxide-dependent killing of intracellular tubercle bacilli. In human monocytes and alveolar macrophages, bacterial lipoproteins similarly activated TLR2 to kill intracellular M. tuberculosis, however by an antimicrobial pathway that is nitric oxide independent. TLR2+CD14+CD68+ macrophages were detected in human lesions of tuberculous lymphadenitis within granulomas and surrounding foci of necrosis. These data provide evidence that mammalian TLRs have retained not only the structural features of Drosophila Toll that allow them to respond to microbial ligands, but also the ability directly to activate antimicrobial effector pathways at the site of infection.

Animals↗
PubMed2005

Regulation of lipopolysaccharide-inducible genes by MyD88 and Toll/IL-1 domain containing adaptor inducing IFN-beta.

Macrophages recognize lipopolysaccharide (LPS) by Toll-like receptor 4 and activate inflammatory responses by inducing expression of various genes. TLR4 activates intracellular signaling pathways via TIR domain containing adaptor molecules, MyD88, and Toll/IL-1 domain containing adaptor inducing IFN-beta (TRIF). Although macrophages lacking MyD88 or TRIF showed impaired cytokine production, activation of intracellular signaling molecules still occurred in response to LPS in these cells. In the present study, we implemented cDNA microarrays to investigate the contribution of MyD88 and TRIF in gene expression induced by LPS stimulation. Whereas wild-type macrophages induced 148 genes in response to LPS, macrophages lacking both MyD88 and TRIF did not upregulate any genes in response to LPS. Surprisingly, 80 LPS-inducible genes were redundantly regulated by either MyD88 or TRIF. In contrast, proinflammatory cytokines and chemokines were critically regulated by MyD88 or TRIF alone. Genes critically regulated by MyD88 alone tend to be induced quickly after LPS stimulation and regulated by mRNA stability as well as transcription. Genes known to be induced by type I interferons were simply dependent on TRIF for their expression. Taken together, MyD88 and TRIF play both redundant and distinct roles in LPS-induced gene expression.

Adaptor Proteins, Signal Transducing↗
PubMed2004

PI3K signaling controls cell fate at many points in B lymphocyte development and activation.

Many receptors on diverse cell types activate phosphoinositide 3-kinase (PI3K). The lipid products of PI3K, termed 3-phosphoinositides, regulate numerous cellular processes by recruiting specific proteins to membrane signaling complexes. In the B lymphocyte lineage, PI3K activation is a critical control point at various stages of development, proliferation and differentiation. PI3K signaling is promoted by stimulatory receptors such as surface immunoglobulin, CD40, Toll-like receptors and cytokine receptors, and opposed by the inhibitory receptor FcgammaRIIB1. Genetic dissection of the PI3K pathway in mice has indicated that certain B cell functions are regulated by a limited set of PI3K isoforms and downstream effectors. Here we review our current understanding of how signals are relayed to and from PI3K in B cells.

Animals↗
PubMed2004

Update in inflammatory bowel disease pathogenesis.

PURPOSE OF REVIEW: During the last few years, significant advances have been achieved in the understanding of the pathogenesis of inflammatory bowel disease (IBD). By gaining new insights, paradigms that seemed to be a safe basis of our knowledge on IBD pathogenesis have recently become doubtful. This review discusses and summarizes the most recent developments. RECENT FINDINGS: Important new insights have been gained into the function of caspase-activating and recruitment domain-15 (CARD15)/NOD2, the first cloned susceptibility gene for Crohn disease (CD). New data on CARD15/NOD2 function and nuclear factor-kappaB activation indicate that an inflammatory reaction of the intestinal mucosa as a response of the innate immune system may be necessary for the maintenance of gut homeostasis. CD may therefore be seen as a defective immune response, no longer only as hyperresponsiveness of the mucosal immune system. Data on CARD15/NOD2 expression suggest that macrophages and epithelial cells could be the site of a primary pathophysiologic defect, and T-cell activation might just be a secondary effect inducing chronification of the inflammation, perhaps as a backup mechanism to a defective innate immunity. In addition to CARD15/NOD2, there are additional "innate" pathways by which commensal and pathogenic bacteria can directly interact with cells of the intestinal mucosa (eg, toll-like receptors). The "germ concept" and the "genetic concept" of IBD pathophysiology are converging. SUMMARY: New findings are changing our concepts of the pathogenesis of IBD. The innate immune system, early responses to bacterial products, and the modulation of T-cell responses are important aspects that are reviewed.

Journal Article↗
PubMed2001

CpG motifs in bacterial DNA and their immune effects.

Unmethylated CpG motifs are prevalent in bacterial but not vertebrate genomic DNAs. Oligodeoxynucleotides (ODN) containing CpG motifs activate host defense mechanisms leading to innate and acquired immune responses. The recognition of CpG motifs requires Toll-like receptor (TLR) 9, which triggers alterations in cellular redox balance and the induction of cell signaling pathways including the mitogen activated protein kinases (MAPKs) and NF kappa B. Cells that express TLR-9, which include plasmacytoid dendritic cells (PDCs) and B cells, produce Th1-like proinflammatory cytokines, interferons, and chemokines. Certain CpG motifs (CpG-A) are especially potent at activating NK cells and inducing IFN-alpha production by PDCs, while other motifs (CpG-B) are especially potent B cell activators. CpG-induced activation of innate immunity protects against lethal challenge with a wide variety of pathogens, and has therapeutic activity in murine models of cancer and allergy. CpG ODN also enhance the development of acquired immune responses for prophylactic and therapeutic vaccination.

Animals↗
PubMed2004

Analogies between Drosophila and mammalian TRAF pathways.

A central event in innate immunity is the activation of the NF-kappaB signaling pathway and up-regulation of NF-kappaB-dependent defense genes. Attack of mammals as well as of insects by microorganisms leads, among other things, to the activation of receptors of the Toll-like receptor group. Various adaptor proteins involving members of the TNF receptor-associated factor (TRAF) family channel these receptor-generated signals to conserved intracellular kinase cascades that finally lead to the activation of NF-kappaB and JNK. In vertebrates, TRAF proteins link these pathways also to IL-1R-related molecules and members of the TNF receptor superfamily, which orchestrate a variety of immunoregulatory processes of the innate but also of the adaptive immune system. In this review, we will focus on the similarities but also the differences in TRAF-dependent signaling pathways of mammals and insects.

Animals↗
PubMed2002

TLR4, but not TLR2, mediates IFN-beta-induced STAT1alpha/beta-dependent gene expression in macrophages.

Toll-like receptor 2 (TLR2) agonists induce a subset of TLR4-inducible proinflammatory genes, which suggests the use of differential signaling pathways. Murine macrophages stimulated with the TLR4 agonist Escherichia coli lipopolysaccharide (LPS), but not with TLR2 agonists, induced phosphorylation of signal transducer and activator of transcription 1alpha (STAT1alpha) and STAT1beta, which was blocked by antibodies to interferon beta (IFN-beta) but not IFN-alpha. All TLR2 agonists poorly induced IFN-beta, which is encoded by an immediate early LPS-inducible gene. Thus, the failure of TLR2 agonists to induce STAT1-dependent genes resulted, in part, from their inability to express IFN-beta. TLR4-induced IFN-beta mRNA was MyD88- and PKR (double-stranded RNA-dependent protein kinase)-independent, but TIRAP (Toll-interleukin 1 receptor domain-containing adapter protein)-dependent. Together, these findings provide the first mechanistic basis for differential patterns of gene expression activated by TLR4 and TLR2 agonists.

Adaptor Proteins, Signal Transducing↗