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At least 937 records · Page 52Linked to original sources
PubMed2005

Ischemia and reperfusion injury in liver transplantation.

Ischemia/reperfusion (I/R) injury is a multifactorial process detrimental to liver graft function. An understanding of the mechanisms involved in I/R injury is essential for the design of therapeutic strategies to improve the outcome of liver transplantation. The generation of reactive oxygen species subsequent to reoxygenation inflicts tissue damage and initiates a cellular cascade leading to inflammation, cell death, and ultimate organ failure. The accruing evidence suggests that Kupffer cells and T cells mediate the activation of neutrophil inflammatory responses. Activated neutrophils infiltrate the injured liver in parallel with increased expression of adhesion molecules on endothelial cells. The heme oxygenase (HO) system is among the most critical of the cytoprotective mechanisms activated during the cellular stress, exerting anti-oxidant and anti-inflammatory functions, modulating the cell cycle, and maintaining the microcirculation. The activation of toll-like receptors (TLR) on Kupffer cells may provide the triggering signal for pro-inflammatory responses in the I/R injury sequence. Indeed, dissecting TLR downstream signaling pathways plays a fundamental role in exploring novel therapeutic strategies based on the concept that hepatic I/R injury represents a case for host "innate" immunity.

Humans↗
PubMed2001

Micrococci and peptidoglycan activate TLR2-->MyD88-->IRAK-->TRAF-->NIK-->IKK-->NF-kappaB signal transduction pathway that induces transcription of interleukin-8.

This study was done to elucidate the signal transduction pathway of interleukin-8 (IL-8) induction by gram-positive bacteria. Bacteria (micrococci) and peptidoglycan (PGN) induced transcription of IL-8 in HEK293 cells expressing Toll-like receptor 2 (TLR2) and CD14 but not in those expressing TLR1 or TLR4. A mutation within the NF-kappaB site in the IL-8 promoter abrogated transcriptional induction of IL-8 by the two stimulants. Dominant negative myeloid differentiation protein (MyD88), IL-1 receptor-associated kinase (IRAK), NFkappaB-inducing kinase (NIK), and IkappaB kinase (IKK) mutant forms completely inhibited micrococcus- and PGN-induced activation of NF-kappaB and expression of the gene for IL-8. Induction of NF-kappaB was partially inhibited by dominant negative tumor necrosis factor receptor-associated kinase 6 (TRAF6) but not TRAF2, whereas induction of IL-8 gene was partially inhibited by both TRAF6 and TRAF2. These data indicate that micrococci and PGN induce TLR2-dependent activation of the gene for IL-8 and that this activation requires MyD88, IRAK, NIK, IKK, and NF-kappaB and may also utilize TRAF6 and, to a lesser extent, TRAF2.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Differential induction of gene promoter constructs by constitutively active human TLRs.

Antigen presenting cells can sense microorganisms through activation of members of the Toll like receptor family (TLRs), which initiate signals leading to transcription of many inflammation-associated genes. TLRs and IL-1R, through their TIR domains, activate NFkappaB and mitogen-activated protein kinase pathways and upregulate a set of specific target genes. Recent evidence points to several differences in signaling pathways activated by individual TLRs. To evaluate the basic signaling potential of individual TIR signaling domains, we generated constitutively active versions of all known human TLRs by fusing mouse CD4 extracellular portion with the TLR transmembrane and TIR domains. A panel of promoters from genes known to be activated by TLRs as well as artificial promoter constructs with transcription factor binding sites were selected to measure their response in the presence of constitutively active CD4TLR fusion molecules. These studies show for the first time that a unique panel of promoters appears to be highly induced by CD4TLR1, 6 (TLRs that usually function through heterodimerisation with TLR2), and CD4TLR10. We also observed that CD4TLR4 is the most potent gene activator compared to all other ten human TLRs. Preliminary analyses of several promoter deletions showed that TLRs use different sequence elements to activate these reporters. In addition, since different ligands for a single TLR (e.g., TLR9) can induce different pathways, the CD4TLR fusions seem to activate all the pathways and therefore can be used to assess the overall signaling capacity of a given TLR. Finally, analysis of promoter constructs induced by the only orphan TLR, TLR10, allowed the identification of the ENA78 promoter as a tool for screening its ligands.

Base Sequence↗
PubMed2006

New insights into the regulation of TLR signaling.

Toll-like receptor (TLR) activation is dictated by a number of factors including the ligand itself and the localization of the receptor, in terms of expression profile and subcellular localization and the signal transduction pathway that has been activated. Recent work into TLR signal transduction has revealed complex regulation at a number of different levels including regulation by phosphorylation, targeted degradation, and sequestration of signaling molecules. Here, we describe recent advances that have been made in our understanding of how TLR signaling is regulated at the biochemical level.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Angelan isolated from Angelica gigas Nakai induces dendritic cell maturation through toll-like receptor 4.

During the evolution of neoplastic diseases, dendritic cell (DC) functions are usually attenuated, and this presents a problem to DC-based immunotherapies against cancer. Here, we investigated the effects of angelan, an acidic polysaccharide isolated from Angelica gigas Nakai, on DC maturation. Angelan efficiently increased the maturation of tlr4(+/+) DCs from C57BL/6 and C3H/HeN mice, but not tlr4(-/-) DCs from C3H/HeJ mice. Phenotypic maturation was confirmed by the elevated expressions of CD80, CD86, and MHC-class II molecules, and functional maturation by increased IL-12 production, enhanced allogenic T cell stimulation, and decreased endocytosis. Angelan was found to activate ERK and NF-kappaB, which are signaling molecules down-stream of toll-like receptor-4 (TLR4) receptors. Angelan-treated mature DC more effectively inhibited B16F10 tumor growth than immature DCs in syngenic murine tumor model. These results indicate that angelan induces DC maturation via TLR4 signaling pathways and suggest the possible use of angelan in DC-based immunotherapies.

Angelica↗
PubMed2003

Differential signaling by CpG DNA in DCs and B cells: not just TLR9.

CpG-containing oligodeoxynucleotides (CpG ODNs) act on Toll-like receptor 9 (TLR9) that is expressed on B cells and plasmacytoid dendritic cells (pDCs) to stimulate the innate immune system, however, different types of CpG ODNs induce distinct responses. Recent papers suggest some CpG ODNs could require a second receptor or cofactor to signal. The different signaling complexes assembled might impact on the affinity with which CpG ODNs signal to TLR9 or activate additional pathways that lead to distinct immune responses.

Animals↗
PubMed2002

Outer membrane protein A (OmpA): a new pathogen-associated molecular pattern that interacts with antigen presenting cells-impact on vaccine strategies.

Outer membrane protein A (OmpA) is a class of proteins highly conserved among the Enterobacteriaceae family and throughout evolution. We have observed that antigen presenting cells (APCs) recognize and are activated by the recombinant OmpA from Klebsiella pneumoniae (KpOmpA). KpOmpA triggers cytokine production by macrophages and dendritic cells (DC), induces DC maturation and signals via Toll-like receptor 2. KpOmpA also interacts with endocytic receptor(s) expressed on DC and macrophages. Tumor antigens coupled to KpOmpA are taken up by APCs and gain access to the MHC class I pathway, triggering the initiation of protective anti-tumor cytotoxic responses in the absence of CD4 T cell help and adjuvant. Thus, OmpA appears as a new type of pathogen-associated molecular pattern (PAMP) usable as a vector in anti-infectious and therapeutic anti-tumor vaccines to elicit CTLs.

Animals↗
PubMed2005

Functional mapping and identification of novel regulators for the Toll/Interleukin-1 signalling network by transcription expression cloning.

Sustained inflammatory responses are central to the development and progression of chronic diseases, including atherosclerosis and rheumatoid arthritis. A large number of stimuli initiate inflammation by acting on Toll-Interleukin-1 related (TIR) domain containing receptors, producing multiple second messengers and thence large scale transcriptional changes. The mechanism by which this activation occurs is complex, and the continuing isolation of novel pathway components, mostly based on sequence similarities and protein-protein interaction studies, suggests that many elements of the TIR-initiated signalling network remain to be identified. Here we use a new technique, allowing identification of components based on function. We report the performance of the screen, our identification of human tribbles as a novel protein family regulating inflammatory signalling networks, and the detection of ten other components with poorly characterized roles in inflammatory signalling pathways. In total, we have identified 28 signalling molecules of diverse molecular mechanism by screening 11% of a cDNA library for the ability to modulation expression of human IL-8, and other molecules remain to be followed up. The results suggest that the number of human genes involved in IL-8 induction pathways exceed 100. The isolation of signalling components by the approach we describe allows detection of new classes of signalling components independent of existing techniques for doing so; it is simple and robust, and constitutes a general method for mapping signal transduction systems controlling gene expression.

3' Untranslated Regions↗
PubMed2005

ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity.

Apoptosis signal-regulating kinase 1 (ASK1) is an evolutionarily conserved mitogen-activated protein 3-kinase that activates both Jnk and p38 mitogen-activated protein kinases. Here we used ASK1-deficient mice to show that ASK1 was selectively required for lipopolysaccharide-induced activation of p38 but not of Jnk or the transcription factor NF-kappaB. ASK1 was required for the induction of proinflammatory cytokines dependent on Toll-like receptor 4 (TLR4) but not TLR2 or other TLRs. Consistent with this, ASK1-deficient mice were resistant to lipopolysaccharide-induced septic shock. Lipopolysaccharide induced the production of intracellular reactive oxygen species, which was required for the formation of a complex of the adaptor molecule TRAF6 and ASK1 and subsequent activation of the ASK1-p38 pathway. Our data demonstrate that the reactive oxygen species-dependent TRAF6-ASK1-p38 axis is crucial for TLR4-mediated mammalian innate immunity.

Animals↗
PubMed2005

Fc receptor gamma-chain activation via hOSCAR induces survival and maturation of dendritic cells and modulates Toll-like receptor responses.

We previously reported the characterization of human osteoclast-associated receptor (hOSCAR), a novel Fc receptor gamma-chain (FcRgamma)-associated receptor expressed by myeloid cells. Here we show that ligation of hOSCAR by specific antibodies promotes dendritic cell (DC) survival by an extracellular signal-regulated kinase (ERK)- and phosphatidylinositol 3-kinase (PI3K)-dependent pathway, linked to expression of the Bcl-2 and Bcl-x(L) antiapoptotic molecules. Crosslinking of hOSCAR leads to maturation of DCs, as demonstrated by up-regulation of maturation markers, decrease in dextran uptake capacity, and secretion of immunesystem effectors such as interleukin-8 (IL-8)/CXC chemokine ligand 8 (CXCL8), IL-12 p40, monocyte chemoattractant protein-1 (MCP-1)/chemokine receptor ligand 2 (CCL2) and macrophage-derived chemokine (MDC)/CCL22. Stimulation of hOSCAR acts in conjunction with the Toll-like receptor (TLR) ligands, lipopolysaccharide (LPS), R-848, and polyinosinic-polycytidylic acid (poly(I:C)), to increase the expression of maturation markers, and to modulate cytokine release. A PI3K-dependent up-regulation of IL-10 release is observed with all the TLR ligands used, whereas regulation of IL-12 production is variable depending on the TLR stimulated. hOSCAR engagement on DCs did not significantly increase the proliferation of naive T cells; however, when co-incubated with TLR ligands, an enhanced proliferation was observed. The percentage of interferon (IFN)-gamma-producing T cells is decreased when hOSCAR engagement is combined with LPS stimulation. Altogether, these data suggest that hOSCAR may modulate the responses of both innate resistance and adaptive immunity.

Antibodies, Monoclonal↗
PubMed2005

Adenosine and cAMP are potent inhibitors of the NF-kappa B pathway downstream of immunoreceptors.

Anergic B lymphocytes exert compromised signal transduction towards the activation of NF-kappa B in response to B cell antigen receptor (BCR) triggering, whereas activation of the ERK pathway appears normal. How this differential down-regulation of the NF-kappa B pathway is regulated remains still elusive. Here, we demonstrate that stimuli known to enhance 3',5'-cyclic adenosine monophosphate (cAMP) are capable of selectively suppressing the activation both of NF-kappa B downstream of the BCR and Toll-like receptor 4 in splenic B lymphocytes and of the high-affinity receptor for IgE in BM-derived mast cells. This suppression is accomplished by blocking phosphorylation and subsequent degradation of the inhibitor of NF-kappa B. A cAMP-dependent protein kinase (PKA) inhibitor reverses this suppressive effect, indicating that PKA is a downstream effector of cAMP in this process. Importantly, not only drugs that artificially elevate intracellular cAMP levels, but also the nucleoside adenosine, which is known to be a mediator of cellular distress, inhibit the NF-kappa B pathway. This suggests that adenosine-mediated signals represent an important step in the molecular decision process controlling inflammation versus anergic immune responses.

1-Methyl-3-isobutylxanthine↗
PubMed2002

Signal integration following Toll-like receptor triggering.

Innate immune cells sense infectious danger through recognition of pathogen-associated molecular patterns (PAMP). Toll-like receptors (TLRs) play a pivotal role in the recognition of PAMP. Although various TLRs with distinct ligand specificities are expressed almost completely and contemporaneously by innate immune cells, and although central key signal transduction pathways of TLRs are shared, the innate response pattern is not uniform. Innate immune cells organize their response dependent on spatial and temporal requirements and mount a pathogen-specific and microbial-adopted reaction. Thus, after triggering of TLRs, complex signaling interactions take place that control and shape the reactivity patterns of innate immune cells. Here we discuss the central signaling pathways of TLRs and their interconnection with other signaling pathways, with emphasis on Janus kinases/signal transducers and activators of transcription JAK/STAT)-dependent intracellular signals. Cis and trans acting signal convergence mechanisms and mutual influence of TLR and cytokine signaling pathways determine the response profile. Hence, in innate immune cells, integration and processing of microbial-dependent and immunologic signals is achieved within individual cells to ascertain an appropriate immune response. Knowledge of these complex mechanisms will help to clarify the critical events during initiation of infection, which in turn may lead to new strategies to control and overcome infectious disease.

Animals↗
PubMed2007

Translational mini-review series on Toll-like receptors: recent advances in understanding the role of Toll-like receptors in anti-viral immunity.

(TLRs) respond to pathogens to initiate the innate immune response and direct adaptive immunity, and evidence to date suggests that they have a role in the detection of viruses. Many viral macromolecules have been shown to activate anti-viral signalling pathways via TLRs, leading to the induction of cytokines and interferons, while viruses also have means of not only evading detection by TLRs, but also of subverting these receptors for their own purposes. This review discusses the role of TLRs in the context of other known viral detection systems, and examines some of the often surprising results from studies using mice deficient in TLRs and their adaptors, in an attempt to unravel the particular contribution of TLRs to anti-viral immunity.

Animals↗
PubMed2006

CpG DNA enhances macrophage cell spreading by promoting the Src-family kinase-mediated phosphorylation of paxillin.

Macrophages are an important component of the innate immune response to infection by microbial pathogens. The activation of macrophages by pathogens is largely mediated by Toll-like receptors (TLRs). Bacterial DNA, which contains unmethylated CpG dinucleotide motifs, is specifically recognised by TLR9 and triggers the activation of a complex network of intracellular signalling pathways that orchestrates the ensuing inflammatory responses of macrophages to the pathogen. Here, we have established that CpG DNA promotes reorganisation of the actin cytoskeleton and enhances cell spreading by primary mouse bone marrow macrophages. CpG DNA stimulation resulted in an approximately 70% increase in cell size. Notably, CpG DNA-induced cell spreading was dependent on the activity of Src-family kinases. Tyrosine phosphorylation of several proteins was increased in a Src-family kinase-dependent manner following CpG DNA stimulation of bone marrow macrophages, including the cytoskeletal protein paxillin. Paxillin was phosphorylated both in vitro and in vivo by the Src-family kinase Hck. Significantly, paxillin from CpG DNA-stimulated bone marrow macrophages had a greater capacity to bind the SH2 domain of the adapter protein Crk than did paxillin from unstimulated bone marrow macrophages. Furthermore, phosphorylation of paxillin by Hck created a binding site for Crk. We propose that the formation of paxillin-Crk complexes may mediate the cytoskeletal changes that underlie the increased cell spreading of macrophages following their activation by CpG DNA.

Animals↗
PubMed2006

17Beta-estradiol downregulates Kupffer cell TLR4-dependent p38 MAPK pathway and normalizes inflammatory cytokine production following trauma-hemorrhage.

Although studies have shown that 17beta-estradiol (estradiol) normalized Kupffer cell function following trauma-hemorrhage, the mechanism by which E2 maintains immune function remains unclear. Activation of Toll-like receptor 4 (TLR4) initiates an inflammatory cascade, involving activation of p38 mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and nuclear factor-kappaB (NF-kappaB). This leads to the release of proinflammatory cytokines. Thus, we hypothesized that the salutary effects of estradiol on Kupffer cell function following trauma-hemorrhage are mediated via negative regulation of TLR4-dependent p38 MAPK and NF-kappaB. TLR4 mutant (C3H/HeJ) and wild type (C3H/HeOuJ) mice were subjected to trauma-hemorrhage (mean BP 35+/-5 mmHg approximately 90 min, then resuscitation) or sham operation. Administration of estradiol following trauma-hemorrhage in wild type mice decreased Kupffer cell TLR4 expression as well as prevented the phosphorylation of p38 MAPK and NF-kappaB. This was accompanied by normalization of Kupffer cell production capacities of IL-6, TNF-alpha, macrophage inflammatory protein (MIP)-1alpha, and MIP-2 and the decrease in plasma cytokine levels. In contrast, TLR4 mutant mice did not exhibit the increase in Kupffer cell p38 MAPK and NF-kappaB activation, cytokine production, or the increase in circulating cytokine levels following trauma-hemorrhage. No difference was observed in activation of PI3K among groups. These results suggest that the protective effect of estradiol on Kupffer cell function is mediated via downregulation of TLR4-dependent p38 MAPK and NF-kappaB signaling following trauma-hemorrhage, which prevents the systemic release of cytokines.

Animals↗
PubMed2006

Myeloid C-type lectins in innate immunity.

C-type lectins expressed on myeloid cells comprise a family of proteins that share a common structural motif, and some act as receptors in pathogen recognition. But just as the presence of leucine-rich repeats alone is not sufficient to define a Toll-like receptor, the characterization of C-type lectin receptors in innate immunity requires the identification of accompanying signaling motifs. Here we focus on the known signaling pathways of myeloid C-type lectins and on their possible functions as autonomous activating or inhibitory receptors involved in innate responses to pathogens or self.

Animals↗
PubMed2004

TRAF6-dependent mitogen-activated protein kinase activation differentially regulates the production of interleukin-12 by macrophages in response to Toxoplasma gondii.

The production of interleukin-12 (IL-12) is critical to the development of innate and adaptive immune responses required for the control of intracellular pathogens. Many microbial products signal through Toll-like receptors (TLR) and activate NF-kappaB family members that are required for the production of IL-12. Recent studies suggest that components of the TLR pathway are required for the production of IL-12 in response to the parasite Toxoplasma gondii; however, the production of IL-12 in response to this parasite is independent of NF-kappaB activation. The adaptor molecule TRAF6 is involved in TLR signaling pathways and associates with serine/threonine kinases involved in the activation of both NF-kappaB and mitogen-activated protein kinase (MAPK). To elucidate the intracellular signaling pathways involved in the production of IL-12 in response to soluble toxoplasma antigen (STAg), wild-type and TRAF6(-/-) mice were inoculated with STAg, and the production of IL-12(p40) was determined. TRAF6(-/-) mice failed to produce IL-12(p40) in response to STAg, and TRAF6(-/-) macrophages stimulated with STAg also failed to produce IL-12(p40). Studies using Western blot analysis of wild-type and TRAF6(-/-) macrophages revealed that stimulation with STAg resulted in the rapid TRAF6-dependent phosphorylation of p38 and extracellular signal-related kinase, which differentially regulated the production of IL-12(p40). The studies presented here demonstrate for the first time that the production of IL-12(p40) in response to toxoplasma is dependent upon TRAF6 and p38 MAPK.

Animals↗
PubMed2006

Structural characterisation and expression analysis of toll-like receptor 2 gene from catfish.

Toll-like receptors (TLRs) are important components of innate immunity. They were found to recognise specific structures on pathogens termed pathogen-associated molecular patterns (PAMPs) and utilise conserved signaling pathways to activate pro-inflammatory cytokines and type-1 interferons. In spite of much understanding gained from the mammalian systems, many fish TLRs are unknown. Recent studies in Japanese flounder as well as in zebrafish suggested that the ligand binding and activation of inflammatory responses in fish may be different from and more complex than those found in mammals. In channel catfish, the major aquaculture species in the United States, only partial sequences of TLR3 and TLR5 were reported. As a part of efforts to characterise the innate immune components in channel catfish, here we cloned and sequenced both the cDNA and the gene for TLR2, a receptor believed mostly responsible for recognition of lipopeptides on the surface of most Gram-positive bacteria. However, expression analysis after infection with a Gram-negative bacterium, Edwardsiella ictaluri indicated that TLR2 was modestly down-regulated in the head kidney tissue of blue catfish, and with a similar pattern in the head kidney of channel catfish though the down-regulation in channel catfish was not statistically significant. In the spleen, an insignificant down-regulation was initially observed early after infection, with an increase of TLR expression later after infection. These results suggest the involvement of TLR2 in the responses after the bacterial infection. As LPS is believed to be the major PAMP for Gram-negative bacteria, additional research is warranted to determine the functions and mechanisms of TLR2 in infections of Gram-negative bacteria.

Amino Acid Sequence↗