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At least 1,117 records · Page 62Linked to original sources
PubMed2004

Lipopolysaccharide signaling induces serum amyloid A (SAA) synthesis in human hepatocytes in vitro.

To investigate the role of lipopolysaccharide (LPS) in hepatocyte activation, we examined the expression of Toll-like receptor 4 (TLR4), the putative receptor for LPS in human hepatocytes. TLR4 mRNA and protein expression was confirmed in human hepatocytes. Stimulation of human hepatocytes with LPS results in rapid degradation of IkappaB-alpha and mitogen activated protein kinase activation. Human hepatocytes stimulated by LPS produced serum amyloid A protein. Our data suggest that human hepatocytes utilize components of TLR4 signal transduction pathways in response to LPS and these direct LPS-mediated effects on hepatocytes may contribute to liver inflammation and injury.

Cells, Cultured↗
PubMed1994

The IL-1 receptor signaling pathway.

Interleukin-1 (IL-1) exerts pleiotropic effects on a variety of tissues through binding to its receptor. Two distinct types of receptors for IL-1 have been characterized in mouse and human. Most of the IL-1 signal has been shown to be transmitted through type I IL-1R (80 kDa) in T lymphocytes as well as B lymphocytes and monocytes. Type II receptor may act as a suppressor of IL-1 biological activities by competing in binding with type I receptors on the cell surface. Functional studies of the type I IL-1R demonstrated that the cytoplasmic segments, possessing a sequence similarity with the Drosophila Toll gene product or IL-6R beta chain, gp130, are important for transmitting activity that induces cytokine genes. In the past three years, several groups reported that IL-1 and tumor necrosis factor (TNF) rapidly induce sphingomyelin turnover in various types of cells, producing ceramide, which may act as a second messenger molecule in an intracellular signaling cascade. Activation of both acid and neutral sphingomyelinases (SMases) has been suggested, and Schutz et al. proposed that the phosphatidylcholine-phospholipase C/acid SMase pathway is involved in TNF-induced NF-kappa B activation. However, our recent study showed that the NF-kappa B activation is induced by IL-1/TNF in fibroblasts from patients with type A Niemann-Pick disease, with acid SMase deficiency. This finding implies that acid SMase activity is not essential for the activation of NF-kappa B by IL-1/TNF at least in fibroblasts. Other signaling pathways including neutral SMase and unidentified protein kinases may be important for NF-kappa B-mediated cytokine gene activation.

Amino Acid Sequence↗
PubMed2004

Toll-like receptor downstream signaling.

The family of Toll-like receptors (TLRs) senses conserved structures found in a broad range of pathogens, causing innate immune responses that include the production of inflammatory cytokines, chemokines and interferons. The signal transduction is initiated from the Toll/interleukin-1 receptor (TIR) domain of TLRs after pathogen recognition. Almost all TLRs use a TIR-containing adapter MyD88 to activate a common signaling pathway that results in the activation of NF-kappaB to express cytokine genes relevant to inflammation. Recently, three further TIR-containing adapters have been identified and shown to selectively interact with several TLRs. In particular, activation of the TRIF-dependent pathway confers antiviral responses by inducing anti-viral genes including that encoding interferon-beta. Taken together, these results indicate that the interaction between individual TLRs and the different combinations of adapters directs appropriate responses against distinct pathogens.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Separation and structural analysis of lipoprotein in a lipopolysaccharide preparation from Porphyromonas gingivalis.

Lipopolysaccharide (LPS) preparations from the periodontopathic bacterium Porphyromonas gingivalis (Pg-LPS) are thought to require Toll-like receptor (TLR)2 rather than TLR4, a receptor of Escherichia coli LPS (Ec-LPS), for activation of immune cells. However, we previously reported that P. gingivalis lipid A, an immunostimulatory principal component of LPS, and its synthetic counterpart activate cells through a TLR4-dependent pathway but not via TLR2. In the present study, a lipoprotein from Pg-LPS (Pg-LP) was shown to be a principal component for TLR2-mediated cell activation. Pg-LP was separated by hydrophobic interaction chromatography followed by preparative electrophoresis and identified by internal peptide sequencing as PG1828, a putative lipoprotein encoded in the P. gingivalis genome. The N-terminal structure was characterized as a triacylated lipopeptide using mass spectrometry. Pg-LP, as well as Ec-LPS, was potent in inducing IL-8 production in human gingival fibroblasts. From our results, we propose that Pg-LP is a powerful inflammatory factor of P. gingivalis.

Amino Acid Sequence↗
PubMed2003

Toll-like receptor 2 (TLR2) and TLR4 differentially activate human mast cells.

In the present report we have analyzed whether human normal cord blood-derived mast cells (CBMC) could interact with bacterial products, especially lipopolysaccharide (LPS) from Escherichia coli and peptidoglycan (PGN) from Staphylococcus aureus, known as Toll-like receptor (TLR) 4 and TLR2 agonists, respectively. We found that both LPS and PGN induced significant release of not only tumor necrosis factor-alpha (TNF-alpha), but also IL-5, IL-10 and IL-13 by human mast cells (MC). We also established that the stimulation of CBMC with LPS or with PGN is mediated through interactions with TLR4 or with TLR2, respectively. Thus, our data indicate that activation of either TLR2 or TLR4 pathway may lead to a pro-Th2 immune response. However, the release of TNF-alpha induced by LPS, conversely to PGN, required the priming of CBMC by IL-4 and the presence of serum components, in particular soluble CD14. Of interest, stimulation by PGN, but not by LPS, induced release of histamine by human MC. Altogether, these findings provide the first evidence that human MC differentially respond towards bacterial components, and that their responses depend on TLR pathways and reveal human specificities in the pattern of cytokine production.

Cells, Cultured↗
PubMed2002

Safflower polysaccharides activate the transcription factor NF-kappa B via Toll-like receptor 4 and induce cytokine production by macrophages.

Two active polysaccharide fractions (SF1 and SF2) purified from dried safflower petals (Carthamus tinctorius L.) stimulated the synthesis of various cytokines by peritoneal macrophages. In a number of cell types, SF1 and SF2 induced a rapid degradation of IkappaB alpha essential for the activation of the transcription factor NF-kappaB. Toll-like receptor 4 (TLR4), but not TLR2, was expressed in all cell lines that responded to SF1 and SF2. Enforced expression of TLR4 and MD-2 rendered responsiveness to SF1 and SF2. Moreover, these safflower polysaccharides failed to induce the production of TNF-alpha and NO by peritoneal macrophages prepared from C3H/HeJ mice that have a point mutation in the Tlr4 gene. Thus, these observations clearly indicate that safflower polysaccharides activate the NF-kappaB signaling pathway via TLR4.

Animals↗
PubMed2004

A20 is a potent inhibitor of TLR3- and Sendai virus-induced activation of NF-kappaB and ISRE and IFN-beta promoter.

Toll-like receptor 3 (TLR3) recognizes dsRNA generated during viral infection and activation of TLR3 results in induction of type I interferons (IFNs) and cellular anti-viral response. TLR3 is associated with a TIR domain-containing adapter protein TRIF, which activates distinct downstream pathways leading to activation of NF-kappaB and ISRE sites in the promoters of type I IFNs. We show here that A20, a NF-kappaB-inducible zinc finger protein that has been demonstrated to be an inhibitor of TNF-induced NF-kappaB activation and a physiological suppressor of inflammatory response, potently inhibited TLR3- and Sendai virus-mediated activation of ISRE and NF-kappaB and IFN-beta promoter in reporter gene assays. A20 also inhibited TRIF-, but not its downstream signaling components TBK1-, IKKbeta-, and IKKepsilon-mediated activation of ISRE and NF-kappaB and IFN-beta promoter. Moreover, A20 interacted with TRIF in co-immunoprecipitation experiments. Finally, expression of A20 could be induced at protein level by Sendai virus infection. These data suggest that A20 targets TRIF to inhibit TLR3-mediated induction of IFN-beta transcription and functions as a feedback negative regulator for TLR3 signaling and cellular anti-viral response.

Adaptor Proteins, Vesicular Transport↗
PubMed2003

TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-beta induction.

Human Toll-like receptor (TLR) 3 recognizes double-stranded (ds) RNA and induces production of interferon (IFN)-beta independent of the adaptor molecules MyD88 and TIRAP. Thus, another adaptor must exist that preferentially mediates TLR3-dependent production of IFN-beta. We have identified an alternative adaptor, designated Toll-interleukin 1 receptor domain (TIR)-containing adaptor molecule (TICAM)-1, that can physically bind the TIR domain of TLR3 and activate the IFN-beta promoter in response to poly(I):poly(C). Thus, dsRNA-TLR3-dependent production of IFN-beta is mediated mainly by TICAM-1. This TICAM-1-dependent pathway may have a role in other TLR-IFN-beta pathways, which form part of the MyD88-independent cellular immune response.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Oxidized low density lipoprotein and innate immune receptors.

PURPOSE OF REVIEW: Atherosclerosis is now recognized as a chronic inflammatory disease. This review discusses recent literature reporting that innate immune receptors bind oxidatively modified LDL and its many oxidized moieties and consequently modulate the atherogenic process. These innate pattern recognition receptors are known to play a central role in pro-inflammatory responses to bacteria by binding pathogen-associated molecular patterns. It is hypothesized that oxidized LDL exposes similar molecular patterns recognized by receptors of innate immunity. RECENT FINDINGS: Minimally modified LDL and its oxidized phospholipids have been found to bind to CD14 or activate Toll-like receptors on macrophages. In turn, various biological activities have been induced, including the stimulation of cytoskeletal rearrangements that alter phagocytic activity and the stimulation of cytokine secretion, such as IL-8. These findings link modified LDL with innate pattern recognition receptors, such as those involved in the lipopolysaccharide signaling pathway. Human epidemiological studies support the involvement of CD14 and TLR4 in cardiovascular diseases. Oxidized LDL has also been demonstrated to bind to C-reactive protein, an opsonic molecule activating classic complement pathway and Fcgamma receptor endocytosis. These data suggest that C-reactive protein may not only be a strong predictor of clinical disease, but may also play a role in atherogenesis. Recent data on other innate immune receptors are discussed in the context of their potential interactions with oxidized LDL and atherogenesis. SUMMARY: Recent findings suggest that oxidized forms of LDL interact with innate immune receptors. Further studies are needed to identify the role of these interactions in inflammation and atherosclerosis.

Animals↗
PubMed2006

The effect of ciprofloxacin on CD14 and toll-like receptor-4 expression on human monocytes.

CD14/toll-like receptor (TLR)-4 complex on monocytes/macrophages can bind lipopolysaccharide (LPS) and transduce the signals intracellularly. An antibacterial drug, ciprofloxacin (CIP), has been reported to modulate the inflammatory and immune responses. In the present study, we examined the effects of CIP on the LPS-induced activation of monocytes isolated from human peripheral blood mononuclear cells (PBMC). CIP suppressed the expression of CD14, TLR-4, intercellular adhesion molecule (ICAM)-1, B7.1, B7.2, and CD40 and the production of tumor necrosis factor (TNF)-alpha induced by LPS in monocytes. CIP induced the production of prostaglandin (PG)E2 and increased intracellular cyclic adenosine monophosphate (cAMP) levels. Cyclooxygenase (COX)-2 inhibitors, NS398 and indomethacin, reversed the effects of CIP on TNF-alpha production and reduced the levels of different surface antigens, whereas a protein kinase A (PKA) inhibitor, H89, did not. Therefore, CIP might regulate the TNF-alpha production induced by LPS by inhibiting the expression of LPS receptor complex, which seems to be mediated by COX-2 but not the cAMP/PKA pathway.

Antigens, CD↗
PubMed2006

Glycopeptidolipids from Mycobacterium avium promote macrophage activation in a TLR2- and MyD88-dependent manner.

The Toll-like receptors (TLRs) are key components in the immune response against numerous pathogens. Previous studies have indicated that TLR2 plays an essential role in promoting immune responses against mycobacterial infections. Prior work has also shown that mice deficient in TLR2 are more susceptible to infection by Mycobacterium tuberculosis, Mycobacterium bovis bacillus Calmette-Guerin, and Mycobacterium avium. Therefore, it is important to define the molecules expressed by pathogenic mycobacteria, which bind the various TLRs. Although a number of TLR agonists have been characterized for M. tuberculosis, no specific TLR ligand has been identified in M. avium. We have found that glycopeptidolipids (GPLs), which are highly expressed surface molecules on M. avium, can stimulate the nuclear factor-kappaB pathway as well as mitogen-activated protein kinase p38 and Jun N-terminal kinase activation and production of proinflammatory cytokines when added to murine bone marrow-derived macrophages. This stimulation was dependent on TLR2 and myeloid differentiation primary-response protein 88 (MyD88) but not TLR4. M. avium express apolar and serovar-specific (ss)GPLs, and it is the expression of the latter that determines the serotype of a particular M. avium strain. It is interesting that the ssGPLs activated macrophages in a TLR2- and MyD88-dependent manner, and no macrophage activation was observed when using apolar GPLs. ssGPLs also differed in their ability to activate macrophages with Serovars 1 and 2 stimulating inhibitor of kappaB p38 and phosphorylation and tumor necrosis factor alpha (TNF-alpha) secretion, while Serovar 4 failed to stimulate p38 activation and TNF-alpha production. Our studies indicate that ssGPLs can function as TLR2 agonists and promote macrophage activation in a MyD88-dependent pathway.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Double-stranded RNAs from the helminth parasite Schistosoma activate TLR3 in dendritic cells.

Stimulation of dendritic cells (DCs) by the egg stage of the helminth parasite Schistosoma mansoni activates a signaling pathway resulting in type I interferon (IFN) and IFN-stimulated gene (ISG) expression. Here, we demonstrate that S. mansoni eggs disjointedly activate myeloid differentiation factor 88 (MyD88)-dependent and MyD88-independent pathways in DCs. Inflammatory cytokine expression and NF-kappa B activation in DCs from MyD88-deficient mice were impaired, whereas signaling transducer activator of transcription (STAT) 1(Tyr701) phosphorylation and ISG expression were intact in MyD88 or Toll-like receptor (TLR)4-deficient counterparts. Accordingly, we analyzed distinct TLR members for their ability to respond to schistosome eggs and established that TLR3 resulted in the activation of NF-kappa B and the positive regulatory domain III-I site from IFN-beta promoter. Unexpectedly, egg-derived RNA possessed RNase A-resistant and RNase III-sensitive structures capable of triggering TLR3 activation, suggesting the involvement of double-stranded (ds) structures. Moreover, DCs from TLR3-deficient mice displayed a complete loss of signaling transducer activator of transcription 1 phosphorylation and ISG expression in response to egg-derived dsRNA. Finally, TLR3-deficient DCs showed a reduced response to schistosome eggs relative to wild-type cells. Collectively, our data suggest for the first time that dsRNA from a non-viral pathogen may act as an inducer of the innate immune system through TLR3.

Animals↗
PubMed2005

Immune responses to dsRNA: implications for gene silencing technologies.

Nucleic acid-induced gene silencing, such as RNA interference (RNAi), induces a multitude of responses in addition to the knockdown of a gene. This is best understood in the context of the antiviral immune response, from which the processes of RNAi are thought to be derived. Viral challenge of a vertebrate host leads to an intricate series of responses that orchestrate antiviral immunity. The success of this multifaceted system in overcoming viral encounters hinges on complex pathogen-host interactions. One aspect of these interactions, the nucleic acid-based immune response, is key to the successful resolution of a viral challenge. In particular, dsRNA, a nucleic acid associated with viral replication, is involved in numerous interactions contributing to induction, activation and regulation of antiviral mechanisms. Specifically, dsRNA is responsible for stimulating important protective responses, such as the activation of dicer-related antiviral pathways, induction of type 1 IFN, and stimulation of dsRNA-activated protein kinase and oligoadenylate synthetase. Furthermore, the modulation and shaping of this overall immune response is facilitated through nucleic acid interactions with pattern recognition receptors such as toll-like receptor 3. These diverse dsRNA-induced antiviral responses have implications for biotechnologies that use dsRNA to harness one arm of the host antiviral machinery for silencing a specific target gene. The interlinked nature of these response elements means that it may be difficult to completely isolate one element from the other arms of the antiviral response program of an organism. Thus, it is beneficial to understand all aspects of the immune response to dsRNA in order to manipulate these systems and minimize unwanted non-specific effects.

Animals↗
PubMed2001

MAP kinase activation in macrophages.

Stimulation of macrophages by a variety of agents causes activation of mitogen-activated protein kinases (MAPKs). Activation of MAPKs by lipopolysaccharide involves CD14 and Toll receptors. Subsequent steps still remain to be explored. Tumor necrosis factor-alpha (TNF-alpha)-induced activation of MAPKs has been shown to involve the death domain proteins (TRADD, FADD, MADD) and TRAFs. Other molecules involved in this pathway include the protein kinases, ASK1, germinal center kinase (GCK), hematopoietic progenitor kinase 1 (HPK1), and GCK-related kinase (GCKR). Although, these pathways have been described in various cell types, their role in macrophages remains to be established. The availability of knockout mice and constitutively active and dominant-negative mutants of MAPKs should greatly enhance our understanding of this field. The activation of MAPKs seems to be different in cell lines compared with primary cells. Among the macrophages, cells from different compartments show different expression of receptors and signal transduction molecules. These differences may account for differences in MAPK activation and other phenotypic differences in macrophages from different compartments. Therefore, it is important to use primary cells for studying MAPK signal-transduction pathways, and the data from cell lines should not be extrapolated to primary cells.

Animals↗
PubMed2003

Therapeutic targeting of Toll-like receptors for inflammatory and infectious diseases.

Roles for Toll-like receptors (TLRs) are emerging in conditions such as sepsis syndrome, systemic lupus erythromatosis, rheumatoid arthritis and asthma, suggesting that the selective targeting of TLRs might be useful therapeutically. TLRs are defined by the presence of extracellular leucine-rich repeats and an intracellular Toll/interleukin-1 receptor domain, and play a role in host defence and inflammation. Signalling pathways activated by TLRs show remarkable similarity to those activated by the pro-inflammatory cytokine interleukin-1 (the receptor for which also has a Toll/interleukin-1 receptor domain), although adaptor proteins specific for certain TLRs are starting to emerge (e.g. Mal and Trif). The common signalling pathways used by all members of the TLR superfamily are being targeted, with drugs that block nuclear factor-kappaB and p38 mitogen-activated protein kinase in clinical development for diseases such as rheumatoid arthritis and psoriasis. As we learn more about TLR signal transduction, more options are presenting themselves for pharmacological targeting.

Animals↗
PubMed2003

Activation of toll-like receptor 2 (TLR2) and TLR4/MD2 by Neisseria is independent of capsule and lipooligosaccharide (LOS) sialylation but varies widely among LOS from different strains.

Lipooligosaccharide (LOS) structure and capsular polysaccharide of Neisseria meningitidis each greatly influence the virulence of the organism and the quality of host innate immune responses. In this study, we found that production of the proinflammatory cytokine tumor necrosis factor (TNF) by a human monocyte-derived cell line (THP-1) exposed to strains of N. meningitidis lacking capsule and/or with truncated LOS was similar to that elicited by the isogenic wild-type strain. These mutants also exhibited no difference in induction of the interleukin-8 (IL-8) promoter in a transfected HeLa cell system of Toll-like receptor 2 (TLR2) and TLR4/MD2 signaling. However, purified LOS from diverse strains of Neisseria (both N. meningitidis and N. gonorrhoeae) caused widely variant levels of IL-8 promoter induction in cells expressing MD2 that correlated with the production of TNF from THP-1 cells. These data suggest that although modification of the oligosaccharide chain of LOS and/or absence of capsule do not affect cell signaling mediated by TLR4/MD2, fine-structural differences in the LOS do influence signaling through TLR4/MD2 and, through this pathway, influence some of the proinflammatory responses elicited by Neisseria.

Bacterial Capsules↗
PubMed2006

C-type lectins on dendritic cells and their interaction with pathogen-derived and endogenous glycoconjugates.

Human C-type lectin receptors (CLRs) characteristically bind glycosylated ligands in a Ca(2+)-dependent way via their carbohydrate recognition domain (CRD). Their carbohydrate preference is dependent on the amino acid sequence in the CRD domain and on the ability and flexibility of the CRD domain to accommodate sugar moieties that are located at different distances from each other in the glycoconjugate. Although microbial and vertebrate cells are able to produce similar polysaccharide chains, the density of carbohydrates on microbes is much higher compared to vertebrate cells. Despite this difference, carbohydrates present on both cell types can be recognized by the CLRs. These receptors are predominantly expressed by antigen presenting cells such as dendritic cells. In addition to the Toll-like receptor family, CLRs function as pattern recognition receptors by recognizing glycosylated patterns on pathogens. This usually results in internalization of the pathogen, lysosomal degradation and subsequent loading of pathogen-derived peptides into major histocompatibility complex molecules for antigen presentation. However, several pathogens have developed ways to exploit the CLRs to evade immune eradication by for example escaping from the lysosomal degradation pathway or by inducing anti-inflammatory cytokines. When CLRs bind endogenous glycosylated ligands they mediate several processes like cell-cell adhesion and clearance of aberrant cells like tumor cells or apoptotic cells.

Amino Acid Sequence↗