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At least 595 records · Page 33Linked to original sources
PubMed2004

Signal transduction in rheumatoid arthritis.

PURPOSE: Signal transduction pathways are the intracellular mechanism by which cells respond and adapt to environmental stress. Understanding the critical networks in diseases like rheumatoid arthritis can potentially identify novel therapeutic targets. RECENT FINDINGS: Dissecting the complex pathways involved in rheumatoid synovitis, including mitogen-activated protein kinases, NF-kB, tumor suppressors, Janus kinases, the signal transducer and activator of transcription, suppressors of cytokine stimulation, and toll-like receptors may lead to new approaches to inflammatory arthritis. For instance, targeting NF-kB via IkB kinase 2 with specific inhibitors may block an array of proinflammatory cytokines that contribute to synovitis. Inhibition of Janus kinases and p38 could block metalloproteinase expression and protect the extracellular matrix. Overexpression of suppressors of cytokine stimulation and inhibition of signal transducer and activator of transcription are additional approaches that have demonstrated efficacy in animal models of arthritis. Tumor suppressor proteins and cell cycle inhibitors represent additional targets with unexpected anti-inflammatory activities. Recent evidence also suggests that targeting toll-like receptors may regulate cytokine expression in rheumatoid arthritis. SUMMARY: Multiple signal transduction pathways have been implicated in rheumatoid arthritis, and preclinical models have confirmed the therapeutic potential of small molecule inhibitors. Orally bioavailable inhibitors of the mitogen-activated protein kinase and NF-kB pathways have been designed and are currently being evaluated. Many other pathways could be targeted and offer new therapeutic options for rheumatoid arthritis.

Arthritis, Rheumatoid↗
PubMed2004

Toll-like receptor 9-dependent and -independent dendritic cell activation by chromatin-immunoglobulin G complexes.

Dendritic cell (DC) activation by nucleic acid-containing immunoglobulin (Ig)G complexes has been implicated in systemic lupus erythematosus (SLE) pathogenesis. However, the mechanisms responsible for activation and subsequent disease induction are not completely understood. Here we show that murine DCs are much more effectively activated by immune complexes that contain IgG bound to chromatin than by immune complexes that contain foreign protein. Activation by these chromatin immune complexes occurs by two distinct pathways. One pathway involves dual engagement of the Fc receptor FcgammaRIII and Toll-like receptor (TLR)9, whereas the other is TLR9 independent. Furthermore, there is a characteristic cytokine profile elicited by the chromatin immune complexes that distinguishes this response from that of conventional TLR ligands, notably the induction of BAFF and the lack of induction of interleukin 12. The data establish a critical role for self-antigen in DC activation and explain how the innate immune system might drive the adaptive immune response in SLE.

Animals↗
PubMed2005

Pathogen recognition with Toll-like receptors.

The innate immune system is an evolutionarily conserved system of defense against microbial infections. The family of Toll-like receptors is a major class of receptors that sense molecular patterns associated with a broad range of pathogens including bacteria, viruses, fungi and protozoa. Following pathogen recognition, Toll-like receptors initiate intracellular signal transduction that results in the expression of genes involved in inflammation, antiviral responses and maturation of dendritic cells. Individual Toll-like receptors activate common and unique transcription factors through different signaling pathways to drive specific biological responses against microorganisms.

Animals↗
PubMed2006

Ubiquitin: tool and target for intracellular NF-kappaB inhibitors.

The transcription factor nuclear factor-kappaB (NF-kappaB) has a pivotal role in initiating inflammation and raising an effective immune response. Because NF-kappaB activation depends on ubiquitination, cells have developed ubiquitin (Ub)-mediated strategies for inhibiting NF-kappaB activation and preventing excessive inflammation. Recent findings concerning tumor necrosis factor (TNF) receptor and toll-like receptor (TLR)-interleukin-1 (IL-1) receptor signalling pathways show that Ub can be a tool as well as a target for NF-kappaB inhibitory proteins, either by labelling specific signalling proteins for proteasome-dependent degradation or by serving as a target for specific de-ubiquitinating enzymes that prevent the formation of pertinent signalling complexes. Interfering with ubiquitination therefore seems to be a versatile means for regulating NF-kappaB activity, indicating that studies of Ub-mediated signalling might hold the key for developing new therapeutic strategies for inflammatory disease.

Animals↗
PubMed1998

A role for the Drosophila Toll/Cactus pathway in larval hematopoiesis.

In the Drosophila larva, blood cells or hemocytes are formed in the lymph gland. The major blood cell type, called plasmatocyte, is small, non-adhesive and phagocytic. Plasmatocytes differentiate into adhesive lamellocytes to form multilayered capsules around foreign substances or, in mutant melanotic tumor strains, around self tissue. Mutations in cactus or Toll, or constitutive expression of dorsal can induce lamellocyte differentiation and cause the formation of melanotic capsules. As maternally encoded proteins, Toll, Cactus and Dorsal, along with Tube and Pelle, participate in a common signal transduction pathway to specify the embryonic dorsal-ventral axis. Using the maternal pathway as a paradigm, we investigated if these proteins have additional roles in larval hemocyte formation and differentiation. Analysis of cactus mutants that lack Cactus protein revealed that almost all of these animals have an overabundance of hemocytes, carry melanotic capsules and die before reaching pupal stages. In addition, the lymph glands of cactus larvae are considerably enlarged. The number of mitotic cells in the cactus and TollD hemolymph is higher than that in the wild-type hemolymph. The hemocyte density of mutant Toll, tube or pelle hemolymph is significantly lower than that of the wild type. Lethality of mutant cactus animals could be rescued either by the selective expression of wild-type Cactus protein in the larval lymph gland or by the introduction of mutations in Toll, tube or pelle. Cactus, Toll, Tube and Pelle proteins are expressed in the nascent hemocytes of the larval lymph gland. Our results suggest that the Toll/Cactus signal transduction pathway plays a significant role in regulating hemocyte proliferation and hemocyte density in the Drosophila larva. These findings are discussed in light of similar hematopoietic functions of Rel/I(kappa)B-family proteins in mice.

Animals↗
PubMed2006

[Recognition of viral nucleic acids and regulation of type I IFN expression].

Recognition of viral nucleic acids with pattern recognition receptors (PRRs) is the first step to induce innate immune system. Type I interferons (IFNs), central mediators in the antiviral innate immunity, are responsible for induction of cytokines and chemokines that disrupt virus replication. Recent studies indicated that there are at least two distinct pathways for the induction of type I IFN by viral infection. Toll-like receptors (TLRs) are extracellular and endosomal PRRs for microbial pathogens whereas retinoic acid inducible gene-I(RIG-I) and melanoma differentiation-associated gene 5(MDA5) are novel intracellular PRRs for viral dsRNA. In this report we describe the distinct mechanisms inducing type I IFNs through TLRs and RIG-I/MDA5 pathways.

Animals↗
PubMed2006

Gene-expression profiling of HIV-1 infection and perinatal transmission in Botswana.

Perinatal transmission of human immunodeficiency virus (HIV)-1 represents a major problem in many regions of the world, especially Southern Africa. With the exception of viral and proviral load, the role for maternal cofactors in perinatal transmission outcome is largely unknown. In this study, an assessment was made of peripheral blood mononuclear cells (PBMC) gene-expression profiles to better understand transcriptional changes associated with HIV-1 infection and perinatal transmission among young adult mothers with infants in Botswana. Peripheral blood mononuclear cells specimens were used from 25 HIV+ drug naive and 20 HIV- healthy mothers, similar in age and location, collected in 1999-2000 and 2003, and processed with the exact same methods, as previously described. Expression profiling of 22 277 microarray gene probes implicated a broad initiation of innate response gene-sets, including toll-like receptor, interferon-stimulated and antiviral RNA response pathways in association with maternal HIV-1 infection. Maternal transmission status was further associated with host genes that influence RNA processing and splicing patterns. In addition to real-time polymerase chain reaction validation of specific genes, enriched category validation of PBMC profiles was conducted using two independent data sets for either HIV-1 infection or an unrelated RNA virus, severe acute respiratory virus infection. HIV-1 pathogen-specific host profiles should prove a useful tool in infection and transmission intervention efforts worldwide.

Adolescent↗
PubMed2003

Gamma interferon augments the intracellular pathway for lipopolysaccharide (LPS) recognition in human intestinal epithelial cells through coordinated up-regulation of LPS uptake and expression of the intracellular Toll-like receptor 4-MD-2 complex.

Although some intestinal epithelial cell lines are known to respond to lipopolysaccharide (LPS), understanding of the relationship between LPS responsiveness and the expression of LPS receptors or factors regulating LPS responsiveness of intestinal epithelial cell lines is incomplete. In this study, we demonstrate that commonly studied human intestinal epithelial cell lines can be classified into at least three different types on the basis of LPS responsiveness, Toll-like receptor-4 (TLR4) expression, and the effects of gamma interferon (IFN-gamma) on LPS responsiveness. The first phenotype, which includes the HCT-116 and Caco-2 cell lines, is characterized by relative hyporesponsiveness to LPS and diminished expression of TLR4 protein. In these cells, IFN-gamma does not induce LPS responsiveness. The second phenotype, which includes cell line SW480, exhibits a highly LPS-responsive phenotype and surface expression of TLR4 protein even in unprimed conditions. These lines are functionally similar to cells of monocytic lineage. In the third phenotype, which includes the HT-29 and Colo205 cell lines, TLR4 protein is largely present in the cytoplasmic fraction and the cells are hyporesponsive to LPS in an unprimed condition. However, priming of these cells with IFN-gamma can induce LPS responsiveness through augmentation of LPS uptake and expression of MD-2 mRNA and intracellular TLR4 proteins. Finally, these findings suggest that the Th1 cytokine IFN-gamma modulates LPS responsiveness through several mechanisms in intestinal epithelial cells and that these cells may comprise different subpopulations with distinct roles in innate immune responses.

Antigens, Surface↗
PubMed2000

Positional cloning of Lps, and the general role of toll-like receptors in the innate immune response.

In mice (and by inference, in all mammals), a single pathway exists to serve lipopolysaccharide (LPS) signal transduction, and as such, allelic mutations at a single locus entirely abolish responses to LPS in C3H/HeJ and C57BL/10ScCr mice. Positional cloning of this locus, known as Lps, revealed that mutations of the Toll-like receptor 4 gene (Tlr4) are responsible for endotoxin resistance. A quick succession of studies have shown Tlr4 to be the critical transmembrane component of the LPS signal transduction complex. As LPS sensing by Tlr4 depends on physical contact between the two molecules, Tlr4 is a direct interface with the microbial world. Eight other molecules with strong similarity to Tlr4 are presently known in mammals, and taking Tlr4 as a model, all may be guessed to participate in the early detection of invasive pathogens. Acting together, the Toll-like receptors may be assumed to present macrophages with a comprehensive "picture" of the micobial world, and thus comprise the principal sensing molecules utilized by cells of the innate immune system.

Animals↗
PubMed2004

Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection.

Several subsets of dendritic cells have been shown to produce type I IFN in response to viral infections, thereby assisting the natural killer cell-dependent response that eliminates the pathogen. Type I IFN production can be induced both by unmethylated CpG-oligodeoxynucleotide and by double-stranded RNA. Here, we describe a codominant CpG-ODN unresponsive phenotype that results from an N-ethyl-N-nitrosourea-induced missense mutation in the Tlr9 gene (Tlr9(CpG1)). Mice homozygous for the Tlr9(CpG1) allele are highly susceptible to mouse cytomegalovirus infection and show impaired infection-induced secretion of IFN-alpha/beta and natural killer cell activation. We also demonstrate that both the Toll-like receptor (TLR) 9 --> MyD88 and TLR3 --> Trif signaling pathways are activated in vivo on viral inoculation, and that each pathway contributes to innate defense against systemic viral infection. Whereas both pathways lead to type I IFN production, neither pathway offers full protection against mouse cytomegalovirus infection in the absence of the other. The Tlr9(CpG1) mutation alters a leucine-rich repeat motif and lies within a receptor domain that is conserved within the evolutionary cluster encompassing TLRs 7, 8, and 9. In other TLRs, including three mouse-specific TLRs described in this paper, the affected region is not represented. The phenotypic effect of the Tlr9(CpG1) allele thus points to a critical role for TLR9 in viral sensing and identifies a vulnerable amino acid within the ectodomain of three TLR proteins, essential for a ligand response.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Suppressor of cytokine signaling (SOCS) proteins indirectly regulate toll-like receptor signaling in innate immune cells.

Suppressor of cytokine signaling (SOCS) proteins constitute a class of negative regulators for Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways. These intracellular proteins are induced by cytokine signaling, but they can also be induced by stimulation of Toll-like receptors (TLR). It has even been suggested that SOCS proteins are important negative regulators of TLR signaling. Here we have elucidated the nature of the regulatory role of SOCS in TLR signaling. Induction of SOCS-3 and cytokine-inducible Src homology 2-containing protein (CIS) by TLR stimulation was strictly dependent on MyD88 but showed differing needs in case of SOCS-1. However, induction of SOCS proteins by TLR ligands was independent of type I interferon. In macrophages overexpressing SOCS, we were not able to observe an inhibitory effect of SOCS-1, SOCS-2, SOCS-3, or CIS on prototypical TLR target genes such as tumor necrosis factor-alpha. However, we found that TLR-2, TLR-3, TLR-4, and TLR-9 stimulation induced interferon-beta (IFN-beta), which is able to exert auto- and paracrine signaling, leading to the activation of secondary genes like IP-10. SOCS-1 and, to a lesser extent, SOCS-3 and CIS were able to inhibit this indirect signaling pathway following TLR stimulation, whereas neither MAP kinase nor NF kappa B signaling were affected. However, STAT-1 tyrosine phosphorylation following TLR triggering was severely impaired by SOCS-1 overexpression. Thus, our data suggest that SOCS proteins induced by TLR stimulation limit the extent of TLR signaling by inhibiting type I IFN signaling but not the main NF kappa B pathway.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Disabling surveillance: bacterial type III secretion system effectors that suppress innate immunity.

Many Gram-negative bacterial pathogens of plants and animals are dependent on a type III protein secretion system (TTSS). TTSSs translocate effector proteins into host cells and are capable of modifying signal transduction pathways. The innate immune system of eukaryotes detects the presence of pathogens using specific pathogen recognition receptors (PRRs). Plant PRRs include the FLS2 receptor kinase and resistance proteins. Animal PRRs include Toll-like receptors and nucleotide-binding oligomerization domain proteins. PRRs initiate signal transduction pathways that include mitogen-activated protein kinase (MAPK) cascades that activate defence-related transcription factors. This results in induction of proinflammatory cytokines in animals, and hallmarks of defence in plants including the hypersensitive response, callose deposition and the production of pathogenesis-related proteins. Several type III effectors from animal and plant pathogens have evolved to counteract innate immunity. For example, the Yersinia YopJ/P cysteine protease and the Pseudomonas syringae HopPtoD2 protein tyrosine phosphatase inhibits defence-related MAPK kinase activity in animals and plants respectively. Thus, type III effectors can suppress signal transduction pathways activated by PRR surveillance systems. Understanding targets and activities of type III effectors will reveal much about bacterial pathogenicity and the innate immune system in plants and animals.

Animals↗
PubMed2005

Early onset of inflammation and later involvement of TGFbeta in Duchenne muscular dystrophy.

OBJECTIVE: To identify stage-specific induction of molecular pathology pathways in Duchenne muscular dystrophy (DMD). METHODS: We performed mRNA profiling using muscles from fetopsies, infants (aged 8 to 10 months), and symptomatic patients (aged 5 to 12 years) with DMD, and age- and sex-matched controls. We performed immunohistochemistry to determine changes at the protein level and protein localization. RESULTS: Activated tissue dendritic cells, expression of toll-like receptor 7, and strong induction of nuclear factor-kappaB pathways occurred soon after birth in DMD muscle. Two muscle wasting pathways, atrogin-1 and myostatin, were not induced at any stage of the disease. Normal muscle showed accumulation of glycolytic and oxidative metabolism capacity with increased age, but this accumulation failed in DMD. The transforming growth factor (TGF)-beta pathway was strongly induced in symptomatic patients, with expression of TGFbeta type II receptor and apoptosis signal-regulating kinase 1 proteins on subsets of mature DMD myofibers. CONCLUSIONS: Our data show stage-specific remodeling of human dystrophin-deficient muscle, with inflammatory pathways predominating in the presymptomatic stages and acute activation of TGFbeta and failure of metabolic pathways later in the disease.

Child↗
PubMed2004

Phosphoinositide 3-kinase and Akt occupy central roles in inflammatory responses of Toll-like receptor 2-stimulated neutrophils.

Neutrophils are critical initiators and effectors of the innate immune system and express Toll-like receptor 2 (TLR2) and TLR4. Although signaling through pathways involving phosphoinositide 3-kinase (PI3-K) and the downstream kinase Akt (protein kinase B) plays a central role in modulating neutrophil chemotaxis and superoxide generation in response to engagement of G protein-coupled receptors, the importance of these kinases in affecting inflammatory responses of neutrophils stimulated through TLR2 has not been examined. In these experiments, we found activation of Akt in neutrophils stimulated with the TLR2-specific ligands peptidoglycan and the lipopeptide tri-palmitoyl-S-glyceryl-Cys-Ser-(Lys)(4) that occurred earlier and was of greater magnitude than that present after exposure to the TLR4 agonist LPS. The release of the proinflammatory mediators TNF-alpha and macrophage inflammatory protein-2 was inhibited in a dose-dependent manner by PI3-K blockade. The IC(50) for inhibition of peptidoglycan-stimulated Akt activation and macrophage inflammatory protein-2 release correlated closely, indicating linkage of these two events. PI3-K blockade did not inhibit nuclear translocation of NF-kappa B, but did prevent Ser(536) phosphorylation of the p65 subunit of NF-kappa B, an event required for maximal transcriptional activity of NF-kappa B. Inhibition of PI3-K also prevented activation of p38 mitogen-activated protein kinase and extracellular receptor-activated kinase 1/2 in TLR2-stimulated neutrophils. These results demonstrate that the PI3-K-Akt axis occupies a central role in TLR2-induced activation of neutrophils.

Animals↗
PubMed2003

Nuclear factor-kappaB and its role in sepsis-associated organ failure.

Nuclear factor (NF)-kappaB is involved in regulating the transcription of many of the immunomodulatory mediators involved in the development of sepsis-induced organ failure. Kinase pathways involving p38 and Akt and initiated by engagement of Toll-like receptors modulate transcriptional activity of NF-kappaB, but apparently through different mechanisms. Increased activation of NF-kappaB occurs with sepsis, and greater levels of nuclear accumulation of NF-kappaB are associated with higher rates of mortality and worse clinical outcome. The percentage of apoptotic neutrophils is reduced in sepsis, and inhibition of nuclear translocation of NF-kappaB restores neutrophil apoptosis to baseline levels. In models of sepsis, suppression of NF-kappaB activation decreases acute inflammatory processes and organ dysfunction. Because NF-kappaB occupies a central role in signaling pathways important in sepsis, modulation of NF-kappaB activity may be an appropriate therapeutic target in patients with sepsis.

Animals↗
PubMed2005

Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF.

Toll-like receptors (TLRs) bind pathogen-specific ligands early in infection, initiating signaling pathways that lead to expression of multiple protective cellular genes. Many viruses have evolved strategies that block the effector mechanisms induced through these signaling pathways, but viral interference with critical proximal receptor interactions has not been described. We show here that the NS3/4A serine protease of hepatitis C virus (HCV), a virus notorious for its ability to establish persistent intrahepatic infection, causes specific proteolysis of Toll-IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF or TICAM-1), an adaptor protein linking TLR3 to kinases responsible for activating IFN regulatory factor 3 (IRF-3) and NF-kappaB, transcription factors controlling a multiplicity of antiviral defenses. NS3/4A-mediated cleavage of TRIF reduces its abundance and inhibits polyI:C-activated signaling through the TLR3 pathway before its bifurcation to IRF-3 and NF-kappaB. This uniquely broad mechanism of immune evasion potentially limits expression of multiple host defense genes, thereby promoting persistent infections with this medically important virus.

Adaptor Proteins, Vesicular Transport↗
PubMed2006

Synthetic triacylated lipid A derivative activates antigen presenting cells via the TLR4 pathway and promotes antigen-specific responses in vivo.

Triggering the maturation of dendritic cells (DC) with toll-like receptor (TLR) agonists is a favored strategy for the development of vaccine adjuvants. The triacyl pseudo-dipeptidic agent OM-197-MP-AC mimicking the lipid A structure of endotoxin induces the maturation of human monocyte-derived DC. In this study we investigated the signaling pathway by which this molecule activates DC. The ability of OM-197-MP-AC to induce maturation of human and mouse DC and macrophages was dependent on TLR4, not TLR2. Ovalbumin-specific humoral and T helper cell responses were significantly augmented by OM-197-MP-AC treatment. Taken together these results indicate that OM-197-MP-AC is a TLR4 agonist inducing DC maturation and represents a novel class of vaccine adjuvants devoid of the known pyrogenic effects associated with classical LPS derivatives.

Acylation↗