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PubMed2000

Nuclear factor-kappa B activation and innate immune response in microbial pathogen infection.

Human pathogenic microorganisms have developed a variety of strategies to infect the host organism successfully, whereas the host has evolved a series of defense mechanisms. In most cases, the epithelial cell layer represents the first barrier for the bacterial pathogen and triggers the innate and inflammatory responses in the host. Epithelial cells release proinflammatory mediators including cytokines and chemokines, leading to the subsequent attraction of monocytes/macrophages. Therefore, epithelial cells represent an immediate-early warning system in the host organism. Subsequent to the colonization of the epithelial layer, invasive microbial pathogens often induce an acute inflammatory response, which functions to activate residential macrophages and recruits blood leukocytes to the site of infection. Distinct receptors of the Toll family on the cell surface of immune cells mediate antibacterial responses in mammals as well as in Drosophila. One of the most important cellular factors involved in the regulation of the host innate antimicrobial response is the immediate-early response transcription factor nuclear factor (NF)-kappa B. Microbial pathogens activate cellular signal transduction pathways that induce NF-kappa B activation, but pathogens also find ways to overcome the innate immune response through active manipulation of the NF-kappa B signal transduction pathways. Exploration of the mechanisms that influence NF-kappa B activity could contribute to a better understanding of the molecular pathogenesis of microbial infections and could be important for potential therapeutic intervention that may be relevant in a wide variety of inflammatory diseases.

Animals↗
PubMed2002

Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors.

Autoreactive B cells are present in the lymphoid tissues of healthy individuals, but typically remain quiescent. When this homeostasis is perturbed, the formation of self-reactive antibodies can have serious pathological consequences. B cells expressing an antigen receptor specific for self-immunoglobulin-gamma (IgG) make a class of autoantibodies known as rheumatoid factor (RF). Here we show that effective activation of RF+ B cells is mediated by IgG2a-chromatin immune complexes and requires the synergistic engagement of the antigen receptor and a member of the MyD88-dependent Toll-like receptor (TLR) family. Inhibitor studies implicate TLR9. These data establish a critical link between the innate and adaptive immune systems in the development of systemic autoimmune disease and explain the preponderance of autoantibodies reactive with nucleic acid-protein particles. The unique features of this dual-engagement pathway should facilitate the development of therapies that specifically target autoreactive B cells.

Adaptor Proteins, Signal Transducing↗
PubMed2003

The interleukin-1 receptor/Toll-like receptor superfamily: signal transduction during inflammation and host defense.

The signal transduction pathways activated by the proinflammatory cytokine interleukin-1 (IL-1) have been the focus of much attention because of the important role that IL-1 plays in inflammatory diseases. A number of proteins have been described that participate in the post-receptor activation of the transcription factor nuclear factor kappaB (NF-kappaB), and stress-activated protein kinases such as p38 mitogen-activated protein kinase (MAPK). It has also emerged that the type I IL-1 receptor (IL-1RI) is a member of an expanding receptor superfamily. These related receptors all have sequence similarity in their cytosolic regions. The family includes the Drosophila melanogaster protein Toll, the IL-18 receptor (IL-18R), and 10 Toll-like receptors (TLRs), TLR-1 to TLR-10, which bind to microbial products, activating host defense responses. Because of the similarity of IL-1RI to Toll, the conserved sequence in the cytosolic region of these proteins has been termed the Toll-IL-1 receptor (TIR) domain. The same proteins activated during signaling by IL-1RI also participate in signaling by other receptors with TIR domains. The receptor superfamily is evolutionarily conserved; members also occur in plants and insects, where they also function in host defense. The signaling proteins that are activated are also conserved across species. Differences are, however, starting to emerge in signaling pathways activated by different receptors. This receptor superfamily, therefore, represents an ancient signaling system that is a critical determinant of the innate immune and inflammatory responses.

Animals↗
PubMed2005

Toll-like receptor 4 signaling regulates cytosolic phospholipase A2 activation and lipid generation in lipopolysaccharide-stimulated macrophages.

Inflammatory lipid mediators such as prostaglandins and leukotrienes play crucial roles in the pathogenesis of bacterial lipopolysaccharide (LPS)-induced inflammation. Cytosolic phospholipase A(2) (cPLA(2)) is a key enzyme in the generation of pro-inflammatory lipid mediators. Here, we found that Toll-like receptor 4 (TLR4) is essential for LPS-induced cPLA(2) activation and lipid release. Inhibition of TLR4 protein expression by TLR4 small interfering RNA or neutralization of TLR4 by the specific antibody against TLR4/MD2 blocked cPLA(2) phosphorylation and cPLA(2)-hydrolyzed arachidonic acid release. Furthermore, activation of the TLR4 signaling pathway by LPS regulated cPLA(2) activation and lipid release. cPLA(2) phosphorylation and cPLA(2)-hydrolyzed lipid release were significantly impaired when TLR4 adaptor protein, either MyD88 or TRIF, was knocked down in LPS-stimulated macrophages. Similarly, LPS-induced arachidonate release was inhibited in cells transfected with a dominant-negative MyD88 or TRIF construct. Subsequently, cPLA(2) activation could be suppressed by inhibition of the TLR4 adaptor protein-directed p38 and ERK MAPK pathways. These findings suggest that, in LPS-induced inflammation, the TLR4-mediated MyD88- and TRIF-dependent MAPK pathways result in cPLA(2) activation and production of pro-inflammatory lipid mediators.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Dendritic cell maturation by innate lymphocytes: coordinated stimulation of innate and adaptive immunity.

Pathogen recognition by Toll-like receptors (TLRs) on dendritic cells (DCs) leads to DC maturation and the initiation of adaptive immunity. Recent studies have shown that innate lymphocytes--natural killer (NK), natural killer T (NKT), and gammadelta T cells--also trigger DC maturation. This interaction in turn expands and activates innate lymphocytes and initiates adaptive T cell immunity. Here, we comment on the evidence that these pathways are TLR independent and have the potential to respond to infection, malignancy, and immunotherapy.

Animals↗
PubMed2006

Endothelial cell activation by mast cell mediators.

Mast cells are important cells of the immune system, and their secretory products regulate many vascular functions. Although considerable interest is focused on the role of mast cells and infectious agents in atherosclerosis, whether or not mast cell mediators act in concert with bacterial agents to regulate endothelial activation is not known. Here, we have described experimental techniques and presented related results to demonstrate how mast cell granule (MCG) mediators and bacterial products synergize endothelial cell inflammatory responses. The described methods outline: (1) the collection of rat peritoneal mast cells; (2) preparation of MCGs; (3) co-culture of human endothelial cells with mast cell granules; (4) determination of the regulation of endo- thelial cell inflammatory responses; (5) demonstration of the role of MCG protease and histamine in the regulation of endothelial cell function; (6) amplification of lipopolysaccharide-induced signal transduction pathways by mast cell granules; (7) elucidation of histamine-induced amplification of endothelial cell responses to Gram-negative and Gram-positive bacterial cell wall components; and (8) determination of the expression of Toll-like receptor 2 and 4. We hope the techniques described here can be used for designing experiments focusing on the regulatory role of mast cell mediators on cell functions.

Animals↗
PubMed2005

Functional characterization of full-length TLR3, IRAK-4, and TRAF6 in zebrafish (Danio rerio).

Recently, the zebrafish, Danio rerio, has been recognized as a useful model for infectious disease and immunity. The Toll-like receptor (TLR) family is an evolutionarily conserved component of the innate immune system that responds to specific pathogen-associated molecular patterns (PAMPs) during an infection. This study reports the identification and characterization of a full-length orthologue of mammalian TLR3, and the key TLR pathway signaling molecules IRAK-4 and TRAF6 in the zebrafish. Sequence analysis of zebrafish TLR3 (zfTLR3), IRAK-4 (zfIRAK-4), and TRAF6 (zfTRAF6) revealed conserved domains shared with insect and mammalian genes. Quantitative real-time PCR showed that all three genes are expressed in a variety of adult tissues and during embryonic development. In in situ hybridization, we showed that zfTLR3, zfIRAK-4, and zfTRAF6 are present in distinct regions of the developing brain at 22hpf and that zfTRAF6 was observed in the developing medial neural tube. Overexpression of zfIRAK-4, zfTRAF6, or a mutant zfTLR3 construct was able to stimulate NF-kappaB activation in ZFL cells as measured by a cotransfected NF-kappaB-luciferase reporter plasmid. Messenger RNA expression profiles of each gene in zebrafish embryos and adults were examined by quantitative real-time PCR following infection with snakehead rhabdovirus (SHRV) or Edwardsiella tarda. Following exposure to SHRV, only zfTLR3 and zfTRAF6 mRNA transcripts were upregulated. Interestingly, exposure of fish to E. tarda resulted in an unexpected increase in mRNA expression of zfTLR3, as well as the anticipated upregulation of zfIRAK-4 and zfTRAF6 mRNA transcripts. These results demonstrate that zebrafish possess conserved TLR-signaling pathways, further emphasizing the utility of the zebrafish as a model for vertebrate immunology.

Amino Acid Sequence↗
PubMed2003

Chlamydia pneumoniae induces tissue factor expression in mouse macrophages via activation of Egr-1 and the MEK-ERK1/2 pathway.

Recent studies have suggested that infection with Chlamydia pneumoniae (C pneumoniae) may contribute to the instability of atherosclerotic plaques and thrombosis and is associated with acute coronary events. Tissue factor (TF), a potent prothrombotic molecule, is expressed by macrophages and other cell types within atherosclerotic lesions and plays an essential role in thrombus formation after plaque rupture. Therefore the effects of C pneumoniae on induction of TF expression in macrophages were investigated. Infection of RAW mouse macrophages with C pneumoniae induced a time-dependent increase in procoagulant activity, expression of TF protein, and TF mRNA. C pneumoniae infection stimulated increased binding of nuclear proteins to the consensus DNA sequence for Egr-1, a key response element within the TF promoter, and increased the expression of Egr-1 protein. Transient transfections of RAW cells with mutated TF promoter constructs showed that the Egr-1 binding region is an important transcriptional regulator of C pneumoniae-induced TF expression. Furthermore, C pneumoniae-stimulated phosphorylation of ERK1/2 and Elk-1 and pharmacological inhibition of mitogen-activated protein kinase activity reduced the expression of TF and Egr-1. Antibody and polymyxin B blocking of the Toll-like receptor 4 (TLR4) partially reduced the C pneumoniae-induced expression of TF and Egr-1. In conclusion, the C pneumoniae-induced increase in TF expression in macrophages is mediated in part by Egr-1, signaling through TLR4, and activation of the MEK-ERK1/2 pathway.

Animals↗
PubMed2005

Phagosome maturation proceeds independently of stimulation of toll-like receptors 2 and 4.

Toll-like receptors modulate many aspects of the innate immune response. Recent reports suggest that the maturation of phagosomes following particle uptake is modulated through signaling of Toll-like receptors. In the current study, the kinetics of phagosome maturation was evaluated quantitatively by ratio fluorometry to determine the lumenal pH of the phagosomes and a FRET-based technique to determine the degree of phagosome/lysosome fusion. Profiles generated for phagosomes containing experimental particles with or without the TLR ligands Pam3Cys-Ser-(Lys)4 or LPS failed to reveal a difference in maturation despite activating TLR-signaling pathways. Moreover, while macrophages defective in individual TLRs generated phagosome maturation profiles identical to wild-type macrophages, MyD88-deficient macrophages exhibited a marked depression in phagosome/lysosome fusion that appears independent of short-term TLR-mediated effects. The results demonstrate that the rate of maturation of phagosomes proceeds independently of TLR signaling pathways.

Adaptor Proteins, Signal Transducing↗
PubMed2026

Comprehensive Landscape of Post-Translational Modification Alterations in Nephrolithiasis Revealing Activation of Multiple Cell Death Pathways.

Nephrolithiasis is a common urinary disorder characterized by high prevalence and recurrence, but the molecular mechanisms underlying calcium oxalate (CaOx)-crystal-induced renal injury remain incompletely understood. We applied integrated proteomic, phosphoproteomic, acetylomic, and lactylomic analyses to kidney tissues from a mouse model of CaOx nephrolithiasis followed by bioinformatic analysis and experimental validation. We identified 658 differentially expressed proteins, 735 differential phosphorylation sites, 335 differential acetylation sites, and 113 differential lactylation sites. Functional enrichment indicated immune activation, fibrotic remodeling, and alterations in PI3K-Akt, NOD-like receptor, p53, and Toll-like receptor signaling together with changes in fatty acid degradation, the tricarboxylic acid cycle, and glycolysis. Kinase activity prediction suggested the relative activation of multiple cyclin-dependent kinases. Proteins associated with ferroptosis, autophagy, necroptosis, and pyroptosis, including ACSL4, BNIP3, RIPK3, and GSDMD, showed coordinated abundance and modification changes. Several candidate sites, including MTOR_S1849, GCLM_K94, GCLM_S59, and GSS_K172, were also dysregulated. These data provide a multiomics resource for CaOx nephrolithiasis and identify candidate PTM events and regulatory pathways for future mechanistic validation.

Animals↗
PubMed2005

Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by pathogenic autoantibodies against nucleoproteins and DNA. Here we show that DNA-containing immune complexes (ICs) within lupus serum (SLE-ICs), but not protein-containing ICs from other autoimmune rheumatic diseases, stimulates plasmacytoid DCs (PDCs) to produce cytokines and chemokines via a cooperative interaction between Toll-like receptor 9 (TLR9) and FcgammaRIIa (CD32). SLE-ICs transiently colocalized to a subcellular compartment containing CD32 and TLR9, and CD32+, but not CD32-, PDCs internalized and responded to SLE-ICs. Our findings demonstrate a novel functional interaction between Fc receptors and TLRs, defining a pathway in which CD32 delivers SLE-ICs to intracellular lysosomes containing TLR9, inducing a signaling cascade leading to PDC activation. These data demonstrate that endogenous DNA-containing autoantibody complexes found in the serum of patients with SLE activate the innate immune system and suggest a novel mechanism whereby these ICs contribute to the pathogenesis of this autoimmune disease.

Antibodies, Antinuclear↗
PubMed2006

Induction of chemokine and cytokine genes in astrocytes following infection with Theiler's murine encephalomyelitis virus is mediated by the Toll-like receptor 3.

Theiler's murine encephalomyelitis virus (TMEV) infection in the central nervous system (CNS) induces a demyelinating disease similar to human multiple sclerosis. TMEV infection results in activation of various chemokine and cytokine genes that are important in the initiation of an inflammatory response. We have previously shown that the production of these chemokines and cytokines in astrocytes is induced via the NF-kappaB pathway following TMEV and Coxsackie virus infection. In this study, we investigated whether the NF-kappaB-dependent inflammatory responses after TMEV infection is triggered through TLR3 and/or TLR7. The activation of NF-kappaB or IRF/ISRE, as well as the production of both MCP-1/CCL2 and IL-8/CXCL8, was observed in only TLR3-transfected HEK 293 cells, but not in TLR7-tranfected cells. The potential involvement of TLR3 in mouse embryonic fibroblasts and primary astrocytes was further investigated following transfection with wildtype or dominant negative form of TLRs and MyD88, as well as astrocytes from TLR3- and MyD88-deficient mice. Similarly, the activation of transcription factors and chemokine genes is induced in these mouse cells through primarily TLR3 signaling pathway, but not TLR7 or other MyD88-mediated pathways following TMEV infection. However, the TLR3-mediated cellular activation does not appear to affect the level of viral replication in astrocytes. These results strongly suggest that TLR3-signaling by TMEV alone is sufficient to induce the initial inflammatory cytokine responses that could be very important for the outcome of virus-induced encephalitis and/or demyelinating diseases, such as multiple sclerosis.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Toll-like receptor signaling mechanisms involved in dendritic cell activation: potential therapeutic control of T cell polarization.

Dendritic cells (DCs) represent a bridge between innate and adaptive immunity, being the maturation process dependent on the binding of pathogen-associated molecular patterns (PAMPs) to Toll-Like Receptors (TLRs) expressed on their surface. TLRs associated to adaptor proteins, following binding to PAMPs, are able to skew specific immune responses towards the T helper (h)(1)- or the Th(2)-type according to the antigenic stimulation involved. Of note, other receptors different from TLRs are expressed on DCs which are also able to recognize PAMPs. Among them, one should mention the DC-specific ICAM-3-grabbing nonintegrin, the mannose receptor, Dectin-1 (the major beta-glucan receptor) and NOD2. Finally, the possibility to interfere therapeutically with the TLR-dependent and -independent signaling pathways in DCs is reviewed. According to current literature, DC activation, their antigen uptake capacity and migration can be enhanced with different experimental procedures whose use in humans is still under evaluation. However, just recently a probiotic cocktail VSL3, successfully used in patients with pouchitis, seems to act on DCs, promoting abundant release of Interleukin-10 in the gut. These novel therapeutic strategies based on the modulation of the signaling pathways in DCs seem to be encouraging for the treatment of inflammatory and autoimmune diseases.

Dendritic Cells↗
PubMed2003

Host innate defenses in the lung: the role of cytokines.

PURPOSE OF REVIEW: The lung has a unique relationship with the environment. Through evolution the lung has developed strategies to defend itself from microbial invasion. As we encounter increasing multidrug-resistant microorganisms, we need to further our knowledge of innate defense systems in order to design novel strategies to deal with these microbes without inducing over-exuberant inflammation and lung injury. RECENT FINDINGS: The development of lung innate immunity requires microbial molecular pattern recognition by the recently described Toll like receptors, the release of early response cytokines that further activate the 'master switch', nuclear factor-kappaB, leading to amplified host defense to invading microbes. A balance of Type 1 and Type 2 cytokines modulates the intensity of innate immunity. Cytokines/chemokines orchestrate the polarization and transition of innate to adaptive immunity. SUMMARY: The elucidation of the pathways involved in innate immunity and factors controlling the transition to adaptive immunity will improve our understanding of the host response to infection and improve our ability to design new therapies for the treatment of infectious disease.

Chemokines↗
PubMed2003

Recognition of microbial infection by Toll-like receptors.

The Toll-like receptors (TLRs) of the innate immune system detect host invasion by pathogens and initiate immune responses. All of the TLRs use the adaptor MyD88 to transduce a signal; however, two newly identified signaling molecules, TIRAP and TRIF, interact with a subset of the TLRs, suggesting a signaling specificity that may be relevant to the type of infection. Activation of the TRIF pathway, for example, leads to the production of antiviral gene products via the transcription factor, IRF3. In vivo experiments in TLR-deficient mice underscore the importance of TLRs in overcoming infection.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Tumor necrosis factor receptor-associated factor (TRAF) 2 and its role in TNF signaling.

Tumor necrosis factor (TNF) is the prototypic member of the TNF ligand family and has a key role in the regulation of inflammatory processes. TNF exerts its functions by interaction with the death domain-containing TNF-receptor 1 (TNF-R1) and the non-death domain-containing TNF-receptor 2 (TNF-R2), both members of a receptor family complementary to the TNF ligand family. Due to the prototypic features of the TNF receptors and their importance for the regulation of inflammation, the signal transduction mechanisms utilized by these receptors have been extensively studied. Several proteins that interact directly or indirectly with the cytoplasmic domains of TNF-R1 and TNF-R2 have been identified in the recent years giving ideas how these receptors are connected to the apoptotic pathway and the signaling cascades leading to activation of NF-kappaB and JNK. Of special interest are TNF receptor-associated factor (TRAF) 1 and 2, which defines a novel group of adaptor proteins involved in signal transduction by most members of the TNF receptor family, of IL-1 receptor and IL-17 receptor as well as some members of the TOLL-like receptor family. TRAF 2 is currently the best-characterized TRAF family member, having a key role in mediating TNF-R1-induced activation of NF-kappaB and JNK. Moreover, recent studies suggest that TRAF 2 represents an integration point for pro- and antiapoptotic signals. This review focuses on the molecular mechanisms that underlay signal initiation by TNF-R1 and TNF-R2, with particular consideration of the role of TRAF 2, and highlights the importance of this molecule for the integration of such antagonizing pathways as death induction and NF-kappaB-mediated surviving signals.

Animals↗
PubMed2026

Therapeutic effect and anti-inflammatory mechanism of modified Shoutai pills against lipopolysaccharide-induced miscarriage in mice.

OBJECTIVE: To elucidate the anti-inflammatory mechanisms of modified Shoutai pills (, MSTP) in miscarriages, we performed transcriptome sequencing on the decidua and placental tissues of pregnancy mice. METHODS: The therapeutic effects and anti-inflammatory mechanisms of MSTP were studied in mice with lipopolysaccharide (LPS)-induced miscarriage. First, the effects of MSTP on pregnancy outcomes and the maternal-fetal interface, in LPS-induced miscarriage mice were examined. RNA sequencing was used to further investigate gene expression changes in LPS-induced miscarriage mice and to assess the effects of MSTP intervention. Finally, the expression levels of inflammation-related genes in the decidua and placental tissues were determined using quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: A high dose of MSTP significantly decreased the resorption rate (P < 0.05) and reduced apoptosis of the decidua and placental tissues in mice. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses showed that inflammatory and immune-related signals were enriched. qRT-PCR results confirmed that in decidual and placental tissues, MSTP reduced the gene expression levels of toll-like receptor 4 (TLR4), nuclear factor kappa-B (NF-&#x3ba;B), c-Jun N-terminal kinase 1, p38, and tumor necrosis factor-&#x3b1;. CONCLUSIONS: In this study, we demonstrated that MSTP effectively prevented embryo loss with an anti-inflammatory mechanism through downregulation of the TLR4-NF-&#x3ba;B/ MAPK signaling pathway, in LPS-induced miscarriage mice model. To our knowledge, this is the first study to reveal the therapeutic mechanism of MSTP in LPS-induced miscarriage in mice.

Animals↗
PubMed2006

Use of human antigen presenting cell gene array profiling to examine the effect of human T-cell leukemia virus type 1 Tax on primary human dendritic cells.

Human T-cell leukemia virus type 1 (HTLV-1) is etiologically linked to adult T-cell leukemia and a progressive demyelinating disorder termed HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). One of the most striking features of the immune response in HAM/TSP centers on the expansion of HTLV-1-specific CD8(+) cytotoxic T lymphocyte (CTL) compartment in the peripheral blood and cerebrospinal fluid. More than 90% of the HTLV-1-specific CTLs are directed against the viral Tax (11-19) peptide implying that Tax is available for immune recognition by antigen presenting cells, such as dendritic cells (DCs). DCs obtained from HAM/TSP patients have been shown to be infected with HTLV-1 and exhibit rapid maturation. Therefore, we hypothesized that presentation of Tax peptides by activated DCs to naIve CD8(+) T cells may play an important role in the induction of a Tax-specific CTL response and neurologic dysfunction. In this study, a pathway-specific antigen presenting cell gene array was used to study transcriptional changes induced by exposure of monocyte-derived DCs to extracellular HTLV-1 Tax protein. Approximately 100 genes were differentially expressed including genes encoding toll-like receptors, cell surface receptors, proteins involved in antigen uptake and presentation and adhesion molecules. The differential regulation of chemokines and cytokines characteristic of functional DC activation was also observed by the gene array analyses. Furthermore, the expression pattern of signal transduction genes was also significantly altered. These results have suggested that Tax-mediated DC gene regulation might play a critical role in cellular activation and the mechanisms resulting in HTLV-1-induced disease.

Antigen-Presenting Cells↗