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PubMed2004

Lipopeptide epitopes extended by an Nepsilon-palmitoyl-lysine moiety increase uptake and maturation of dendritic cells through a Toll-like receptor-2 pathway and trigger a Th1-dependent protective immunity.

Lipopeptides, a form of peptide immunogens, are currently under intense investigation as human vaccines for many infectious pathogens and cancers. However, the cellular and molecular mechanisms of lipopeptide immunogenicity are only partially understood. We have investigated the influence of the lipid content on the immunogenicity of lipopeptides using the herpes simplex virus type 1 (HSV-1) gD(1-23) peptide as a model antigen. Totally synthetic lipopeptides were constructed by covalent attachment to the peptide backbone of either Nepsilon-palmitoyl-lysine (palmitoyl-lipidated peptide, palmitoyl-LP) or cholesterol-lysine (cholesterol-lipidated peptide, cholesterol-LP). Immunization of mice with the palmitoyl-LP, but not with its cholesterol-LP analog, induced a strong T cell-dependent protective immunity against lethal HSV-1 infection. Analysis of cytokine profiles and IgG2a/IgG1 ratios revealed that a dominant Th1-type immune response was stimulated by the palmitoyl-LP, as opposed to a Th2 response generated by its cholesterol-LP analog. The palmitoyl-LP was efficiently taken up in vitro by immature dendritic cells (DC) in a time- and dose-dependent manner, and induced phenotypic maturation and production of pro-inflammatory cytokines by DC. Finally, DC stimulated with the palmitoyl-LP induced antigen-specific T cell responses through the Toll-like receptor-2 pathway. These findings have important implications for the development of effective lipopeptide immunization strategies against infectious pathogens.

Amino Acid Sequence↗
PubMed2002

Lipopolysaccharide-dependent prostaglandin E(2) production is regulated by the glutathione-dependent prostaglandin E(2) synthase gene induced by the Toll-like receptor 4/MyD88/NF-IL6 pathway.

Macrophages produce a large amount of PGE(2) during inflammation. This lipid mediator modulates various immune responses. PGE(2) acts on macrophages and inhibits production of cytokines such as TNF-alpha and IL-12. Membrane-bound glutathione-dependent PGE(2) synthase (mPGES) has been shown to be a terminal enzyme of the cyclooxygenase-2-mediated PGE(2) biosynthesis. Here we identified mPGES as a molecule that is induced by LPS in macrophages. The expression of mPGES was not induced by LPS in mice lacking Toll-like receptor 4 or MyD88. Furthermore, mice deficient in NF-IL6 showed neither induction of mPGES nor biosynthesis of PGE(2) in response to LPS, indicating that mPGES expression in response to LPS is regulated by a Toll-like receptor 4/MyD88/NF-IL6-dependent signaling pathway. We generated mPGES-deficient mice and investigated the role of mPGES in vivo. The mice showed no augmentation of the PGE(2) production in response to LPS. However, they were not impaired in the LPS-induced production of inflammatory cytokines and showed normal response to the LPS-induced shock. Thus, mPGES is critically involved in the biosynthesis of PGE(2) induced by LPS, but is dispensable for the modulation of inflammatory responses.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Escherichia coli P fimbriae utilize the Toll-like receptor 4 pathway for cell activation.

Fimbriae mediate bacterial attachment to host cells and provide a mechanism for tissue attack. They activate a host response by delivery of microbial products such as lipopolysaccharide (LPS) or through direct fimbriae-dependent signalling mechanisms. By coupling to glycosphingolipid (GSL) receptors, P fimbriae trigger cytokine responses in CD14 negative host cells. Here we show that P fimbriae utilize the Toll-like receptor 4 (TLR4)-dependent pathway to trigger mucosal inflammation. Escherichia coli strains expressing P fimbriae as their only virulence factor stimulated chemokine and neutrophil responses in the urinary tract of TLR4 proficient mice, but TLR4 defective mice failed to respond to infection. Mucosal cells were CD14 negative but expressed several TLR species including TLR4, and TLR4 protein was detected. Infection with P fimbriated bacteria stimulated an increase in TLR4 mRNA levels. The activation signal did not involve the LPS-CD14 pathway and was independent of lipid A myristoylation, as shown by mutational inactivation of the msbB gene. Co-staining experiments revealed that TLR4 and the GSL receptors for P fimbriae co-localized in the cell membrane. The results demonstrate that P fimbriae activate epithelial cells by means of a TLR4-dependent signalling pathway, and suggest that GSL receptors for P fimbriae can recruit TLR4 as co-receptors.

Animals↗
PubMed2006

A toll receptor and a cytokine, Toll5A and Spz1C, are involved in toll antifungal immune signaling in the mosquito Aedes aegypti.

The fungal-specific immune response in the mosquito Aedes aegypti involves the Toll immune pathway transduced through REL1, a homologue of the NF-kappaB transcription factor Drosophila Dorsal. The Toll receptor and its ligand, Spätzle (Spz), link extracellular immune signals to the Toll intracellular transduction pathway. Five homologues to the Drosophila Toll (Toll1) receptor (Toll1A, Toll1B, Toll5A, Toll5B, and Toll4) and three homologues to the Drosophila cytokine Spätzle (Spz1A, 1B, and 1C) were identified from genomic and cDNA sequence data bases. Toll1A, Toll5A, Toll5B, and Spz1A were specifically induced in the mosquito fat body following fungal challenge. This transcriptional up-regulation was mediated by REL1. Spz1C was constitutively expressed in the mosquito fat body, whereas Spz1B and Toll4 were primarily expressed in ovarian tissues of female mosquitoes. The transcripts of Toll1B were only detected in early stages of mosquito embryos. RNA interference knock down of Toll5A and Spz1C resulted in two phenotypes of Aedes Toll/REL1 pathway deficiency: decreased induction of Aedes Serpin-27A following fungal challenge and increased susceptibility to the entomopathogenic fungus Beauveria bassiana. These data suggest that Toll5A and Spz1C function as cytokine receptor systems specific to the Toll receptor-mediated immune response following fungal challenge in the mosquito fat body.

Aedes↗
PubMed2006

Supernatant of Bifidobacterium breve induces dendritic cell maturation, activation, and survival through a Toll-like receptor 2 pathway.

BACKGROUND: Commensal gut bacteria are essential for the development and maintenance of the gut's immune system. Some bacteria strains, such as Lactobacillus and Bifidobacterium species, have been reported to provide protection from allergic and inflammatory bowel diseases. However, the interactions between these commensal bacteria and the immune system are largely unknown. OBJECTIVE: We studied the effects of a supernatant from the culture of B breve C50 (BbC50) on the maturation, activation, and survival of human dendritic cells (DCs). METHODS: DCs were differentiated from human monocytes with IL-4 and GM-CSF for 5 days and cultured with BbC50 supernatant (BbC50SN) or LPS for 2 days. RESULTS: BbC50SN induced DC maturation, with increase in CD83, CD86, and HLA-DR expression. We also showed, for the first time, that BbC50SN prolonged DC survival, with high IL-10 and low IL-12 production compared with that seen in LPS-DCs. Moreover, BbC50SN inhibited the effects of LPS on DCs, both in terms of IL-12 production and in terms of survival. The prolonged DC survival was independent of IL-10 production and nuclear factor kappaB pathway but was associated with an upregulation of Bcl-xL and Phospho-Bad. Finally, BbC50SN induced activation of Toll-like receptor 2 (TLR2)-transfected cells in contrast to TLR4-, TLR7-, and TLR9-transfected cells. CONCLUSION: The supernatant of B breve C50 can induce DC maturation and prolonged DC survival through TLR2, with high IL-10 production. These properties might correspond to a regulatory DC profile, which could limit the excessive TH1 response and control the excessive TH2 polarization observed in atopic newborns.

Bifidobacterium↗
PubMed2003

MyD88 is essential for clearance of Leishmania major: possible role for lipophosphoglycan and Toll-like receptor 2 signaling.

Leishmania major is an obligate intracellular eukaryotic pathogen of mononuclear phagocytes. Invasive promastigotes gain entry into target cells by receptor-mediated phagocytosis, transform into non-motile amastigotes and establish in the phagolysosome. Glycosylphosphatidylinositol-anchored lipophosphoglycan (LPG) is a virulence factor and a major parasite molecule involved in this process. We observed that mice lacking the Toll-like receptor (TLR) pathway adaptor protein MyD88 were more susceptible to infection with L. major than wild-type C57BL/6 mice, demonstrating a central role for this innate immune recognition pathway in control of infection, and suggesting that L. major possesses a ligand for TLR. We sought to identify parasite molecules capable of activating the protective Toll pathway, and found that purified Leishmania LPG, but not other surface glycolipids, activate innate immune signaling pathways via TLR2. Activation of cytokine synthesis by LPG required the presence of the lipid anchor and a functional MyD88 adaptor protein. LPG also induced the expression of negative regulatory pathways mediated by members of thesuppressors of cytokine signaling family SOCS-1 and SOCS-3. Thus, the Toll pathway is required for resistance to L. major and LPG is a defined TLR agonist from this important human pathogen.

Adaptor Proteins, Signal Transducing↗
PubMed1992

Selective nuclear transport of the Drosophila morphogen dorsal can be established by a signaling pathway involving the transmembrane protein Toll and protein kinase A.

Establishment of dorsal-ventral polarity in the early Drosophila embryo requires a concentration gradient of the maternal morphogen dorsal (dl). This concentration gradient is established by selective nuclear transport of dl so that dl protein is present only in ventral nuclei. The activity of 11 genes is required for dl nuclear localization. One of these genes, Toll, encodes a transmembrane protein that appears to play the most direct role in regulating dl localization. We have examined the effects of Toll on dl in cotransfected Schneider cells to gain insight into the nature of the interaction between these proteins. We have found that Toll can enhance the nuclear localization of dl and, independently, the ability of dl to activate transcription once in the nucleus. We present evidence that the signaling pathway from Toll to dl involves protein kinase A (PKA) and that nuclear transport and activation of dl results from phosphorylation of dl by PKA. We discuss the significance of these results with respect both to Drosophila embryogenesis and to the regulation of the mammalian transcription factor NF-kappa B.

Animals↗
PubMed2003

Directed expression of the HIV-1 accessory protein Vpu in Drosophila fat-body cells inhibits Toll-dependent immune responses.

Human immunodeficiency virus 1 (HIV-1) expresses several accessory proteins that manipulate various host-cell processes to achieve optimum replicative efficiency. One of them, viral protein U (Vpu), has been shown to interfere with the cellular degradation machinery through interaction with SCF(beta-TrCP) complexes. To learn more about Vpu function in vivo, we used the genetically tractable fruit fly, Drosophila melanogaster. Our results show that the directed expression of Vpu, but not the non-phosphorylated form, Vpu2/6, in fat-body cells affects Drosophila antimicrobial responses. In flies, the Toll and Imd pathways regulate antimicrobial-peptide gene expression. We show that Vpu specifically affects Toll pathway activation by inhibiting Cactus degradation. Given the conservation of the Toll/nuclear factor-kappa B (NF-kappa B) signalling pathways between flies and mammals, our results suggest a function for Vpu in the inhibition of host NF-kappa B-mediated innate immune defences and provide a powerful genetic approach for studying Vpu inhibition of NF-kappa B signalling in vivo.

Animals↗
PubMed2000

A Drosophila IkappaB kinase complex required for Relish cleavage and antibacterial immunity.

Here we report the identification of a Drosophila IkappaB kinase complex containing DmIKKbeta and DmIKKgamma, homologs of the human IKKbeta and IKKgamma proteins. We show that this complex is required for the signal-dependent cleavage of Relish, a member of the Rel family of transcriptional activator proteins, and for the activation of antibacterial immune response genes. In addition, we find that the activated DmIKK complex, as well as recombinant DmIKKbeta, can phosphorylate Relish in vitro. Thus, we propose that the Drosophila IkappaB kinase complex functions, at least in part, by inducing the proteolytic cleavage of Relish. The N terminus of Relish then translocates to the nucleus and activates the transcription of antibacterial immune response genes. Remarkably, this Drosophila IkappaB kinase complex is not required for the activation of the Rel proteins Dif and Dorsal through the Toll signaling pathway, which is essential for antifungal immunity and dorsoventral patterning during early development. Thus, a yet to be identified IkappaB kinase complex must be required for Rel protein activation via the Toll signaling pathway.

Animals↗
PubMed2005

Integrin activation by bacterial fimbriae through a pathway involving CD14, Toll-like receptor 2, and phosphatidylinositol-3-kinase.

CD11b-CD18 and other integrins play important roles in immunity and inflammation and require prior activation through inside-out signaling to efficiently bind their ligands. We present evidence for a novel TLR2-dependent signaling pathway that leads to CD11b-CD18 activation in human monocytes or neutrophils upon recognition of Porphyromonas gingivalis fimbriae through CD14. The activated binding-state of CD11b-CD18, which involves induction of conformational changes, was monitored through detection of an activation-specific epitope of CD11b. The ability of fimbriae to induce this activation epitope was significantly inhibited by a mAb to TLR2, but not to TLR4 or unrelated surface molecules. Moreover, the ability of fimbriae to activate CD11b-CD18 was significantly inhibited by pharmacological inhibitors of phosphatidylinositol-3-kinase but not of PKC or of p38 mitogen-activated protein kinase. The signaling pathway activated by fimbriae is distinct from that which is activated by N-formyl-Met-Leu-Phe, a prototypical integrin activator, since the former was insensitive to pertussis toxin. This novel function of TLR2 as a signaling receptor for pathogen-induced activation of CD11b-CD18 may play a significant role in infection-driven chronic inflammatory conditions, such as periodontal disease or atherosclerosis, where P. gingivalis has been implicated.

CD11b Antigen↗
PubMed1998

MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways.

The Toll-mediated signaling cascade using the NF-kappaB pathway has been shown to be essential for immune responses in adult Drosophila, and we recently reported that a human homolog of the Drosophila Toll protein induces various immune response genes via this pathway. We now demonstrate that signaling by the human Toll receptor employs an adaptor protein, MyD88, and induces activation of NF-kappaB via the Pelle-like kinase IRAK and the TRAF6 protein, similar to IL-1R-mediated NF-kappaB activation. However, we find that Toll and IL-1R signaling pathways are not identical with respect to AP-1 activation. Finally, our findings implicate MyD88 as a general adaptor/regulator molecule for the Toll/IL-1R family of receptors for innate immunity.

Adaptor Proteins, Signal Transducing↗
PubMed2000

The apoptotic signaling pathway activated by Toll-like receptor-2.

The innate immune system uses Toll family receptors to signal for the presence of microbes and initiate host defense. Bacterial lipoproteins (BLPs), which are expressed by all bacteria, are potent activators of Toll-like receptor-2 (TLR2). Here we show that the adaptor molecule, myeloid differentiation factor 88 (MyD88), mediates both apoptosis and nuclear factor-kappaB (NF-kappaB) activation by BLP-stimulated TLR2. Inhibition of the NF-kappaB pathway downstream of MyD88 potentiates apoptosis, indicating that these two pathways bifurcate at the level of MyD88. TLR2 signals for apoptosis through MyD88 via a pathway involving Fas-associated death domain protein (FADD) and caspase 8. Moreover, MyD88 binds FADD and is sufficient to induce apoptosis. These data indicate that TLR2 is a novel 'death receptor' that engages the apoptotic machinery without a conventional cytoplasmic death domain. Through TLR2, BLP induces the synthesis of the precursor of the pro-inflammatory cytokine interleukin-1beta (IL-1beta). Interestingly, BLP also activates caspase 1 through TLR2, resulting in proteolysis and secretion of mature IL-1beta. These results indicate that caspase activation is an innate immune response to microbial pathogens, culminating in apoptosis and cytokine production.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Challenge of Drosophila melanogaster with Cryptococcus neoformans and role of the innate immune response.

We found that the ingestion of Cryptococcus neoformans by Drosophila melanogaster resulted in the death of the fly but that the ingestion of Saccharomyces cerevisiae or the nonpathogenic Cryptococcus kuetzingii or Cryptococcus laurentii did not. The C. neoformans protein kinase A and RAS signal transduction pathways, previously shown to be involved in virulence in mammals, also played a role in killing Drosophila. Mutation of the Toll immune response pathway, the predominant antifungal pathway of the fly, did not play a role in Drosophila defense following ingestion of the yeast. However, the Toll pathway was necessary for the clearance of C. neoformans introduced directly into the hemolymph of D. melanogaster and for the survival of systemically infected flies.

Animals↗
PubMed2000

Toll-like receptor 2-mediated NF-kappa B activation requires a Rac1-dependent pathway.

Mammalian Toll-like receptors (TLRs) are expressed on innate immune cells and respond to the membrane components of Gram-positive or Gram-negative bacteria. When activated, they convey signals to transcription factors that orchestrate the inflammatory response. However, the intracellular signaling events following TLR activation are largely unknown. Here we show that TLR2 stimulation by Staphylococcus aureus induces a fast and transient activation of the Rho GTPases Rac1 and Cdc42 in the human monocytic cell line THP-1 and in 293 cells expressing TLR2. Dominant-negative Rac1N17, but not dominant-negative Cdc42N17, block nuclear factor-kappa B (NF-kappa B) transactivation. S. aureus stimulation causes the recruitment of active Rac1 and phosphatidylinositol-3 kinase (PI3K) to the TLR2 cytosolic domain. Tyrosine phosphorylation of TLR2 is required for assembly of a multiprotein complex that is necessary for subsequent NF-kappa B transcriptional activity. A signaling cascade composed of Rac1, PI3K and Akt targets nuclear p65 transactivation independently of I kappa B alpha degradation. Thus Rac1 controls a second, I kappa B-independent, pathway to NF-kappa B activation and is essential in innate immune cell signaling via TLR2.

Cell Line↗
PubMed1996

The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults.

The cytokine-induced activation cascade of NF-kappaB in mammals and the activation of the morphogen dorsal in Drosophila embryos show striking structural and functional similarities (Toll/IL-1, Cactus/I-kappaB, and dorsal/NF-kappaB). Here we demonstrate that these parallels extend to the immune response of Drosophila. In particular, the intracellular components of the dorsoventral signaling pathway (except for dorsal) and the extracellular Toll ligand, spätzle, control expression of the antifungal peptide gene drosomycin in adults. We also show that mutations in the Toll signaling pathway dramatically reduce survival after fungal infection. Antibacterial genes are induced either by a distinct pathway involving the immune deficiency gene (imd) or by combined activation of both imd and dorsoventral pathways.

Animals↗
PubMed2007

Inflammation, cancer and chemoresistance: taking advantage of the toll-like receptor signaling pathway.

The association between chronic inflammation and cancer has long been observed. Furthermore, NF-kappaB activation and the subsequent production of cytokines, chemokines, growth factors, and antiapoptotic proteins has been found to be involved in cancer progression and chemoresistance. However, the signals inducing NF-kappaB in cancer cells are still not well understood. Here, we reviewed the association between chronic inflammation and cancer, the role of NF-kappaB and its inhibitors as potential anticancer drugs, and Toll-like receptors as possible signal initiators for NF-kappaB activation and inflammation-induced carcinogenesis and chemoresistance. Furthermore, we propose that, the stimulation of Toll-like receptors by microbial components and/or endogenous ligands may represent the initial signal promoting a proinflammatory environment that will enhance tumor growth and chemoresistance.

Animals↗
PubMed2006

Role of the Toll-like receptor 4/NF-kappaB pathway in saturated fatty acid-induced inflammatory changes in the interaction between adipocytes and macrophages.

OBJECTIVE: Previous studies demonstrated that obese adipose tissue is characterized by increased infiltration of macrophages, suggesting that they might represent an important source of inflammation. Using an in vitro coculture system composed of 3T3-L1 adipocytes and RAW264 macrophages, we previously demonstrated that saturated fatty acids (FAs) and tumor necrosis factor (TNF)-alpha derived from adipocytes and macrophages, respectively, play a major role in the coculture-induced inflammatory changes. METHODS AND RESULTS: Coculture of adipocytes and macrophages resulted in the activation of nuclear factor-kappaB (NF-kappaB), a primary regulator of inflammatory responses, in both cell types. Pharmacological inhibition of NF-kappaB markedly suppressed the coculture-induced production of proinflammatory cytokines and adipocyte lipolysis. Peritoneal macrophages obtained from Toll-like receptor 4 (TLR4) mutant mice exhibited marked attenuation of TNFalpha production in response to saturated FAs. Notably, coculture of hypertrophied adipocytes and TLR4-mutant macrophages resulted in marked inhibition of proinflammatory cytokine production and adipocyte lipolysis. We also observed that endogenous FAs, which are released from adipocytes via the beta3-adrenergic stimulation, resulted in the activation of the TLR4/NF-kappaB pathway. CONCLUSIONS: These findings suggest that saturated FAs, which are released in large quantities from hypertrophied adipocytes via the macrophage-induced adipocyte lipolysis, serve as a naturally occurring ligand for TLR4, thereby inducing the inflammatory changes in both adipocytes and macrophages through NF-kappaB activation.

Adipocytes↗
PubMed2002

The endoplasmic reticulum-resident heat shock protein Gp96 activates dendritic cells via the Toll-like receptor 2/4 pathway.

The heat shock protein Gp96 has been shown to induce specific immune responses. On one hand, this phenomenon is based on the specific interaction with CD91 that mediates endocytosis and results in major histocompatibility complex class I-restricted representation of the Gp96-associated peptides. On the other hand, Gp96 induces activation of professional antigen-presenting cells, resulting in the production of pro-inflammatory cytokines and up-regulation of costimulatory molecules by unknown mechanisms. In this study, we have analyzed the consequences of Gp96 interaction with cells expressing different Toll-like receptors (TLRs) and with bone marrow-derived dendritic cells from mice lacking functional TLR2 and/or TLR4 molecules. We find that the Gp96-TLR2/4 interaction results in activation of nuclear factor kappaB-driven reporter genes and mitogen- and stress-activated protein kinases and induces IkappaBalpha degradation. Bone marrow-derived dendritic cells of C3H/HeJ and more pronounced C3H/HeJ/TLR2(-/-) mice fail to respond to Gp96. Interestingly, activation of bone marrow-derived dendritic cells depends on endocytosis of Gp96 molecules. Our results provide, for the first time, the molecular basis for understanding the Gp96-mediated activation of antigen-presenting cells by describing the simultaneous stimulation of the innate and adaptive immune system. This feature explains the remarkable ability of Gp96 to induce specific immune responses against tumors and pathogens.

Animals↗