Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic inflammation and aberrant lipid metabolism represent hallmarks of atherosclerosis. Innate immunity critically depends upon Toll-like receptor (TLR) signalling. Recent data directly implicate signalling by TLR4 and TLR2 in the pathogenesis of atherosclerosis. The role that TLRs play in the pathogenesis of atherosclerosis can be assessed by using several animal models, which provide a double genetic deficiency in TLRs and molecules implicated in the lipid metabolism, such as ApoE or LDL receptor. Furthermore, a more recent technique, such as the bone marrow transplantation (BMT), can be a useful and straightforward method to elucidate the role of stromal versus hematopoietic cells in the acceleration of the atheroma.
Methods Mol Biol 2009
PMID:Innate immunity, Toll-like receptors, and atherosclerosis: mouse models and methods. 1937 21

Rheumatoid arthritis (RA) is a chronic inflammatory disease that ultimately leads to the progressive destruction of cartilage and bone in numerous joints. There is mounting evidence for an important function of innate immunity in the pathogenesis of RA. Activation of cells by microbial components and also by endogenous molecules via Toll-like receptor (TLR) results in the production of a variety of proinflammatory cytokines, chemokines, and destructive enzymes, some of which can characteristically be found in RA.By immunohistochemistry we found elevated TLR2, 3, and 4 expressions in the rheumatoid synovium. In the synovial lining layer and at sites of invasion into cartilage, RA synovial fibroblasts (RASF) are the major cells expressing TLR2, 3, and 4. Stimulation of cultured RASF in vitro with the TLR2 ligand bacterial lipoprotein (bLP), the TLR3 ligand poly(I-C), and the TLR4 ligand LPS was shown to upregulate IL-6 as well as matrix metalloproteinases (MMPs) 1 and 3. These results suggest an important role for TLR2, 3, and 4 in the activation of synovial fibroblasts in RA leading to chronic inflammation and joint destruction.
Methods Mol Biol 2009
PMID:Toll-like receptors and rheumatoid arthritis. 1937 24

Both ubiquitination and phosphorylation are crucial mediators involved in controlling the functions of numerous proteins belonging to the Toll-like receptor (TLR) signaling pathways. Altering the aforementioned post-translational events can be detrimental to the host survival. Therefore, the importance of these modifications cannot be overestimated. This chapter describes techniques used to examine if a protein is ubiquitinated and/or phosphorylated. In addition, a method is provided to identify the modified amino acids. We have previously shown using these techniques that the protein MyD88 adapter-like (Mal) is phosphorylated and ubiquitinated following activation of the TLR2 and TLR4 signaling pathways. Both post-translational modifications are essential for the activation and degradation of Mal, and thus are crucial steps, in regulating these TLR signaling cascades and consequently the innate immune response.
Methods Mol Biol 2009
PMID:Analysis of ubiquitin degradation and phosphorylation of proteins. 1937 34

The airways are continuously exposed to respiratory pathogens, which may result in bacterial pneumonia, one of the most common infectious diseases and the leading cause of sepsis. Considering that recurrent exposure to microbial products can lead to tolerance of immune cells, and that this might contribute to the susceptibility to nosocomial infection, we investigated the effect of in vivo lipopolysaccharide (LPS) instillation on the responsiveness of alveolar macrophages. In eight healthy humans, sterile saline was instilled into a lung segment by bronchoscope, followed by instillation of LPS into the contralateral lung; 6 hours later, a bilateral bronchoalveolar lavage was performed, and purified alveolar macrophages were ex vivo stimulated with LPS or lipoteichoic acid (LTA), triggering Toll-like receptor (TLR)-4 and -2, respectively. In vivo LPS-exposed alveolar macrophages were primed, as reflected by increased ex vivo LPS- and LTA-induced IL-1 beta and IL-6 gene expression and production compared with in vivo saline-exposed alveolar macrophages. LPS instillation did not influence the surface expression of TLR4 or TLR2. Furthermore, LPS instillation did not impact on the expression of a number of extracellular and intracellular regulators of TLR signaling. However, p38 mitogen-activated protein kinase remained phosphorylated in alveolar macrophages upon LPS instillation. The current data demonstrate that LPS instillation in the human lung primes alveolar macrophages for further stimulation with either LPS or LTA, possibly by sustained p38 mitogen-activated protein kinase activation.
Am J Respir Cell Mol Biol 2010 Mar
PMID:Priming of alveolar macrophages upon instillation of lipopolysaccharide in the human lung. 1944 56

Various strains of mycoplasmas cause activation of transcriptional factor NF-kB as a result of interaction with different combinations of Toll-like receptors (TLR). It is well known that the MALP-2 protein of M. fermentans activates the NF-kB through interaction with the TLR2/6, lipid-associated membrane lipopeptides (LAMPs) of M. penetrans through the TLR1/2, LAMPs of M. pneumoniae through combinations of Toll-like receptors (TLR2/6 and TLR1/2), and superantigene of M. arthritidis through the TLR2 and TLR4-dependent pathways. In this study, we defined specific Toll-like receptors for LAMPs of M. arginini. For carrying out the research we used cell lines 293-null, 293-hTLR2, 293-hTLR1/2, 293-hTLR2/CD14, 293-hTLR2/6, 293-hTLR4/ CD14-MD2 expressing certain combinations of TLR and their coreceptors. It was shown that LAMPs of M. arginini cause activation of NF-kB interacting with TLR2/1, TLR2/6 and TLR2/ CD14, but not with TLR2 alone or TLR4.
Mol Gen Mikrobiol Virusol 2009
PMID:[Lipid-associated membrane lipopeptides of M. arginini activate NF-kB by interacting with TLR2/1, TLR2/6, and TLR2/CD14]. 1951 7

Endothelin-1 (ET-1) is mainly secreted by endothelial cells and acts as a potent vasoconstrictor. In addition ET-1 has also been shown to have pleiotropic effects on a variety of other systems including adaptive immunity. There are two main ET-1 receptors, ET(A) and ET(B), which have different tissue and functional distributions. Dendritic cells (DC) are pivotal antigen-presenting cells linking the innate with the adaptive immune system. DC are sentinels expressing pattern-recognition receptors, e.g. the toll-like receptors (TLR) for detecting danger signals released from pathogens or tissue injury. Here we show for the first time that stimulation of human monocyte-derived DC with exogenous as well as endogenous selective TLR4 and TLR2 agonists induces the production of ET-1 in a dose- and time-dependent manner. 'Alternative' activation of DC in the presence of 1alpha,25-dihydroxyvitamin D(3) results in a marked potentiation of the endothelin response, whereas prostaglandin E(2) or dexamethasone do not increase ET-1 production. Furthermore, chetomin, an inhibitor of the transcription factor hypoxia-inducible factor 1alpha (HIF-1alpha), prevents TLR-mediated secretion of ET-1. Surprisingly, stimulation of human monocytes with LPS does not lead to secretion of detectable amounts of ET-1. These results suggest a role of ET-1 as an important player in human DC biology and innate immunity in general.
Mol Immunol 2009 Sep
PMID:TLR2 and TLR4 agonists induce production of the vasoactive peptide endothelin-1 by human dendritic cells. 1955 83

Legionella bacterium, an intracellular pathogen of mononuclear phagocytes, causes acute fatal pneumonia, especially in patients with impaired cellular immune responses. Until recently, however, the toll-like receptor (TLR) engagement of bacterial proteins derived from Legionella is uncertain. We previously showed that a 19-kDa highly conserved peptidoglycan-associated lipoprotein (PAL) of Legionella pneumophila induced the PAL-specific B cell and T cell responses in mice. In this study, we observed that the rPAL antigen of L. pneumophila, as an effector molecule, activated murine macrophages via TLR2 and produced proinflammatory cytokines such as IL-6 and TNF-alpha. In both BALB/c and TLR4-deficient C3H/HeJ mice, pretreatment of macrophages with anti-TLR2 mAb showed severely impaired cytokine production in response to the rPAL. In addition, in vitro the rPAL treatment increased the cell surface expression of CD40, CD80, CD86 and MHC I/II molecules. We further showed that the synthetic CpG-oligodeoxynucleotides (CpG ODN) coadministered with the rPAL enhanced IL-12 and IL-6 production and expression of CD40, CD80 and MHC II compared to the rPAL treatment alone. In conclusions, these results indicate that Legionella PAL might activate macrophages via a TLR2-dependent mechanism which thus induce cytokine production and expression of costimulatory and MHC molecules.
Exp Mol Med 2009 Oct 31
PMID:Legionella lipoprotein activates toll-like receptor 2 and induces cytokine production and expression of costimulatory molecules in peritoneal macrophages. 1956 4

In this experiment Toll-like receptor expression pattern in monocytes and monocyte-derived macrophages by lipopolysaccharide (LPS) stimulation was examined. Jugular venous blood was collected from four Japanese calves, and the peripheral blood mononuclear cells (PBMCs) were isolated. The cells were directly used for collecting monocytes by magnetic cell sorting or cultured for 7 days to collect monocyte-derived macrophages in Repcell. Then we analyzed the mRNA expression pattern of TLRs and cytokines in monocytes and monocyte-derived macrophages after LPS stimulation for 24 h. LPS stimulation of both monocytes and monocyte-derived macrophages resulted in an increase in the levels of mRNA transcripts for TNF-alpha, IL-6 and IL-8. Moreover, TNF-alpha and IL-6 mRNA expressions were significantly augmented by LPS stimulation in monocyte-derived macrophages. TLRs mRNA expressions were unchanged after LPS stimulation of monocytes, while TLRs mRNA expressions in monocyte-derived macrophages were complicated. TLR1, 3, 5, 8 and 10 were significantly decreased after LPS stimulation and there were no differences in the mRNA expressions of TLR2, 4, 6 and 7 between the groups of control and LPS stimulation. Besides, no expression of TLR9 was found. As antigen presenting cells, monocytes and monocyte-derived macrophages respond differently to LPS, so they may have different functions in the innate immune system.
Cell Mol Immunol 2009 Jun
PMID:Differential responses between monocytes and monocyte-derived macrophages for lipopolysaccharide stimulation of calves. 1956 6

Porin of Shigella dysenteriae type 1 up-regulated Toll-like receptor (TLR)2 on CD3-stimulated CD4(+) T cells but could not induce the expression of other TLRs. TLR2 in association with myeloid differentiating factor 88 (MyD88) triggered the downstream signal transduction pathway leading to activation of mitogen-activated protein kinase (MAPK) and nuclear factor kappaB (NF-kappaB), and degradation of IkappaB, the NF-kappaB inhibitor. TLR2 co-stimulation by porin resulted in T cell expansion by inducing both proliferation and survival of the CD4(+) T cells. Extracellular signal-regulated kinase (ERK)1/2 activation inhibitor U0126 and NF-kappaB translocation inhibitor SN-50 significantly inhibited proliferation of T cells, highlighting a direct role of ERK and NF-kappaB in the process. However, cell survival involving Bcl-X(L) induction was found to be regulated essentially by ERK with no significant role of NF-kappaB. Porin-induced proliferation was supported by induction of IL-2 and CD25 that are known to play a pivotal role in T cell expansion. Apart from inducing T cell proliferation, porin triggered effector functions of the cells, evident from TLR2- and MyD88-dependent release of type 1 cytokines tumor necrosis factor (TNF) and interferon (IFN)-gamma along with the induction of type 1 chemokines macrophage-inflammatory protein (MIP)-1alpha and MIP-1beta and their receptor CCR5. The proliferation, survival and effector function of CD4(+) T cells through TLR2 co-stimulation show the capability of porin to directly turn adaptive immunity into action.
Mol Immunol 2009 Sep
PMID:Porin of Shigella dysenteriae directly promotes toll-like receptor 2-mediated CD4+ T cell survival and effector function. 1957 36

Activation of toll-like receptors (TLRs) leads to derepression and subsequent activation of inflammatory response genes that play essential roles in innate and acquired immunity. Derepression requires signal-dependent turnover of the nuclear receptor corepressor NCoR from target promoters, but the mechanisms remain poorly understood. Here, we report that TLR4 uses NFkappaB to deliver IKKepsilon to target promoters that contain "integrated circuits" of kappaB and AP-1 sites, resulting in local phosphorylation of c-Jun and subsequent NCoR clearance. In contrast, TLR2 signaling leads to rapid activation of CaMKII and phosphorylation of the TBLR1 component of NCoR complexes, bypassing the requirement for c-Jun phosphorylation and enabling NCoR clearance from promoters lacking integrated kappaB elements. Intriguingly, the IKKvarepsilon-dependent clearance pathway is sensitive to transrepression by liver X receptors, while the CaMKII-dependent pathway is not. These findings reveal mechanisms for integration of TLR, calcium, and nuclear receptor signaling pathways that underlie pathogen-specific responses and disease-specific programs of inflammation.
Mol Cell 2009 Jul 10
PMID:Transcriptional integration of TLR2 and TLR4 signaling at the NCoR derepression checkpoint. 1959 15


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