Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0751781 (NOD)
 6,696 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previously, we reported that treatment of T cells with the 60-kDa heat shock protein (HSP60) inhibits chemotaxis. We now report that treatment of purified human T cells with recombinant human HSP60 or its biologically active peptide p277 up-regulates suppressor of cytokine signaling (SOCS)3 expression via TLR2 and STAT3 activation. SOCS3, in turn, inhibits the downstream effects of stromal cell-derived-1alpha (CXCL12)-CXCR4 interaction in: 1) phosphorylation of ERK1/2, Pyk2, AKT, and myosin L chain, required for cell adhesion and migration; 2) formation of rear-front T cell polarity; and 3) migration into the bone marrow of NOD/SCID mice. HSP60 also activates SOCS3 in mouse lymphocytes and inhibits their chemotaxis toward stromal cell-derived factor-1alpha and their ability to adoptively transfer delayed-type hypersensitivity. These effects of HSP60 could not be attributed to LPS or LPS-associated lipoprotein contamination. Thus, HSP60 can regulate T cell-mediated inflammation via specific signal transduction and SOCS3 activation.
 ...
PMID:Heat shock protein 60 activates cytokine-associated negative regulator suppressor of cytokine signaling 3 in T cells: effects on signaling, chemotaxis, and inflammation. 1597 59

The CATERPILLER (CLR, also NOD and NLR) proteins share structural similarities with the nucleotide binding domain (NBD)-leucine-rich repeat (LRR) superfamily of plant disease-resistance (R) proteins and are emerging as important immune regulators in animals. CLR proteins contain NBD-LRR motifs and are linked to a limited number of distinct N-terminal domains including transactivation, CARD (caspase activation and recruitment), and pyrin domains (PyD). The CLR gene, Monarch-1/Pypaf7, is expressed by resting primary myeloid/monocytic cells, and its expression in these cells is reduced by Toll-like receptor (TLR) agonists tumor necrosis factor (TNF) alpha and Mycobacterium tuberculosis. Monarch-1 reduces NFkappaB activation by TLR-signaling molecules MyD88, IRAK-1 (type I interleukin-1 receptor-associated protein kinase), and TRAF6 (TNF receptor (TNFR)-associated factor) as well as TNFR signaling molecules TRAF2 and RIP1 but not the downstream NFkappaB subunit p65. This indicates that Monarch-1 is a negative regulator of both TLR and TNFR pathways. Reducing Monarch-1 expression with small interference RNA in myeloid/monocytic cells caused a dramatic increase in NFkappaB activation and cytokine expression in response to TLR2/TLR4 agonists, TNFalpha, or M. tuberculosis infection, suggesting that Monarch-1 is a negative regulator of inflammation. Because Monarch-1 is the first CLR protein that interferes with both TLR2 and TLR4 activation, the mechanism of this interference is significant. We find that Monarch-1 associates with IRAK-1 but not MyD88, resulting in the blockage of IRAK-1 hyperphosphorylation. Mutants containing the NBD-LRR or PyD-NBD also blocked IRAK-1 activation. This is the first example of a CLR protein that antagonizes inflammatory responses initiated by TLR agonists via interference with IRAK-1 activation.
 ...
PMID:The CATERPILLER protein monarch-1 is an antagonist of toll-like receptor-, tumor necrosis factor alpha-, and Mycobacterium tuberculosis-induced pro-inflammatory signals. 1620 35

Since human gingival fibroblasts are the major cells in periodontal tissues, we hypothesized that gingival fibroblasts are endowed with receptors for bacterial components, which induce innate immune responses against invading bacteria. We found clear mRNA expression of Toll-like receptors (TLR)1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, MD-2, MyD88, NOD1, and NOD2 in gingival fibroblasts. Gingival fibroblasts constitutively expressed these molecules. Upon stimulation with chemically synthesized ligands mimicking microbial products for these receptors, the production of pro-inflammatory cytokines, such as interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1, was markedly up-regulated. Furthermore, the production of pro-inflammatory cytokines induced by TLR and NOD ligands was significantly inhibited by an RNA interference assay targeted to NF-kappaB. These findings indicate that these innate immunity-related molecules in gingival fibroblasts are functional receptors involved in inflammatory reactions in periodontal tissues, which might be responsible for periodontal pathogenesis.
 ...
PMID:Functional TLRs and NODs in human gingival fibroblasts. 1731 57

Epithelial cells may form the first barrier of defense against bacteria in human tissues. We recently revealed that oral epithelial cells generated anti-bacterial factors, such as peptidoglycan recognition proteins (PGRPs) and beta-defensin 2, but not proinflammatory cytokines, such as interleukin-8 (IL-8), upon stimulation with bacterial cell-surface components. In this study, we found clear expressions of Toll-like receptor (TLR)2, TLR3, TLR4, TLR7, NOD1 and NOD2 in oral, tongue, salivary gland, pharyngeal, esophageal, intestinal, cervical, breast, lung, and kidney epithelial cells. However, tongue, salivary gland, pharyngeal, esophageal, intestinal, cervical, breast, lung, and kidney epithelial cells, as well as oral epithelial cells, did not secrete IL-6, IL-8 or monocyte chemoattractant protein-1 in response to chemically synthesized TLR and NOD agonists mimicking microbial components: TLR2 agonistic lipopeptide (Pam3CSSNA), TLR3 agonistic Poly I:C, TLR4 agonistic lipid A (LA-15-PP), TLR7 agonistic single stranded RNA (ssPoly U), NOD1 agonistic iE-DAP (gamma-D-glumtamyl-meso-diaminopimelic acid), and NOD2 agonistic muramyldipeptide (MDP). Although PGRPs on oral epithelial cells were significantly up-regulated upon stimulation with these synthetic components, PGRPs on pharyngeal epithelial cells were only slightly up-regulated, and PGRPs on esophageal, intestinal and cervical epithelial cells were not up-regulated upon stimulation with the components. In contrast, stimulation with synthetic TLRs and NODs ligands induced beta-defensin 2 generation in all epithelial cells examined. These findings indicate that TLR and NOD in various epithelial cells are functional receptors that induce anti-bacterial responses in general without being accompanied by inflammatory responses.
 ...
PMID:Various human epithelial cells express functional Toll-like receptors, NOD1 and NOD2 to produce anti-microbial peptides, but not proinflammatory cytokines. 1740 38

Anti-neutrophil cytoplasmic Abs against proteinase 3 (PR3) have been detected in relation to a wide range of inflammatory conditions, and the interaction of anti-PR3 Abs with leukocytes provokes cell activation, although how is not clear. Flow cytometric analysis revealed an increase in cell-surface CD14, Toll-like receptor (TLR)2, TLR4 and intracellular TLR3, TLR7, TLR8, TLR9, NOD1 and NOD2 expression during anti-PR3 priming in human monocytic THP-1 cells. Anti-RP3 Abs markedly promoted the release of IL-8 induced by chemically synthesized TLR and NOD ligands mimicking bacterial components: TLR2-agonistic lipopeptide (FSL-1), TLR3-agonistic poly I:C, TLR4-agonistic lipid A (LA-15-PP), TLR7/8-agonistic single stranded RNA (ssPolyU), TLR9-agonistic bacterial CpG DNA, NOD1-agonistic FK156/565 and NOD2-agonistic muramyldipeptide (MDP) in THP-1 cells and human peripheral blood mononuclear cells, although sole incubation with anti-PR3 Abs induced only a low level of IL-8. The priming response was evident after 2h of preincubation with anti-PR3 Abs and peaked after 6h. Priming was also observed for the production of TNF-alpha and monocyte chemoattractant protein-1. An RNA interference assay revealed that anti-PR3 Abs activated THP-1 cells in a PR3- and protease-activated receptor-2-dependent manner. Furthermore, the anti-PR3 Ab-mediated cell activation was significantly abolished by RNA interference targeted at PR3 mRNA and by inhibition of phospholipase C and NF-kappaB. These results suggest that anti-PR3 Abs prime human monocytic cells to produce cytokines upon stimulation with various bacterial components by up-regulating the TLR and NOD signaling pathway, and that these mechanisms may actively participate in the inflammatory process.
 ...
PMID:Antibodies to proteinase 3 prime human monocytic cells via protease-activated receptor-2 and NF-kappaB for Toll-like receptor- and NOD-dependent activation. 1745 51

The Idd6 locus on mouse chromosome 6, which controls the development of type 1 diabetes in the NOD mouse, affects proliferation rates of T cells and the activity of regulatory CD4+CD25+ T cells. Using a transcriptional profiling approach, we show that splenocytes and thymocytes from diabetes-resistant Idd6 NOD.C3H-congenic mouse strains exhibit a constitutive and specific down-regulation of Toll-like receptor 1 (Tlr1) gene expression compared with diabetes prone NOD mice. This phenotype correlates with a diminished proliferation capacity of both CD4+CD25- effector and CD4+CD25+ regulatory T cells upon in vitro stimulation of the TLR1/TLR2 pathway by the ligand palmitoyl-3-cysteine-serine-lysine 4, and with the constitutive down-regulation of Tnf-alpha and IL-6 in macrophages of Idd6- congenic mice. These data suggest that TLR1 is involved in the regulation of mechanisms that impinge on diabetes development in the NOD mouse.
 ...
PMID:The type 1 diabetes locus Idd6 controls TLR1 expression. 1778 27

Research into intracellular sensing of microbial products is an up and coming field in innate immunity. Toll-like receptors (TLRs) recognize Brucella spp. and bacterial components and initiate mononuclear phagocyte responses that influence both innate and adaptive immunity. Recent studies have revealed the intracellular signaling cascades involved in the TLR-initiated immune response to Brucella infection. TLR2, TLR4 and TLR9 have been implicated in host interactions with Brucella; however, TLR9 has the most prominent role. Further, the relationship between specific Brucella molecules and various signal transduction pathways needs to be better understood. MyD88-dependent and TRIF-independent signaling pathways are involved in Brucella activation of innate immune cells through TLRs. We have recently reported the critical role of MyD88 molecule in dendritic cell maturation and interleukin-12 production during B. abortus infection. This article discusses recent studies on TLR signaling and also highlights the contribution of NOD and type I IFN receptors during Brucella infection. The better understanding of the role by such innate immune receptors in bacterial infection is critical in host-pathogen interactions.
 ...
PMID:The role of innate immune receptors in the control of Brucella abortus infection: toll-like receptors and beyond. 1866 88

Bacterial peptidoglycan (PGN) has been reported to be sensed by cell-surface Toll-like receptor (TLR)2. On the other hand, intracellular NOD-like receptors recognize PGN partial structures: NOD1 and NOD2 recognize the peptide moiety containing diaminopimelic acid, and the muramyldipeptide (MDP) moiety, respectively. In this study, we examined in human monocytic THP-1 cells the pro-inflammatory cytokine-inducing abilities of PGNs and their fragments enzymatically prepared from Staphylococcus epidermidis ATCC 155: a polymer-type water-soluble PGN possessing an intact glycan chain (SEPS) and a monomer-type PGN (SEPS-M). The water-soluble PGN polymer, SEPS, exhibited considerably stronger activities to induce pro-inflammatory cytokines than parent PGNs and the PGN monomer, SEPS-M. Short interference RNA targeting TLR2 and NOD2 markedly reduced the activities of SEPS. In the same experiments, the activities of PGNs were mainly reduced in TLR2-silenced cells, whereas the activities of SEPS-M as well as a synthetic MDP were markedly reduced in NOD2-silenced cells. Furthermore, the PGNs and a reference PGN from Staphylococcus aureus in combination with MDP synergistically induced interleukin-8 in THP-1 cells. These findings strongly suggested that a polymer-type water-soluble PGN fragment, SEPS, exhibits both TLR2-and NOD2-agonistic activities, which induced the synergistic activation of human monocytic cells.
 ...
PMID:A polymer-type water-soluble peptidoglycan exhibited both Toll-like receptor 2- and NOD2-agonistic activities, resulting in synergistic activation of human monocytic cells. 1880 54

Studies have suggested a correlation between the decline in infectious diseases and increase in the incidence of type 1 diabetes (T1D) in developed countries. Pathogens influence the disease outcome through innate immune receptors such as TLRs. Here we report the effect of ligation of TLR2 and dectin 1 on APCs and the influence of innate immune response induced through these receptors on T1D. Exposure of APCs of NOD mice to zymosan, a fungal cell wall component that interacts with TLR2 and dectin 1, resulted in the release of significant amounts of IL-10, TGF-beta1, IL-2, and TNF-alpha. Treatment of pre- and early hyperglycemic mice with zymosan resulted in suppression of insulitis, leading to a significant delay in hyperglycemia. T cells from zymosan-treated mice showed reduced ability to induce diabetes in NOD-Scid mice compared with control T cells. Zymosan treatment induced suppression of T1D was associated with an increase in the L-selectin(high) T cell frequencies and enhanced suppressor function of CD4(+)CD25(+) T regulatory cells. Further, activation by anti-CD3-Ab induced larger amounts of TGF-beta1 and/or IL-10 production by CD4(+)CD25(+) and CD4(+)CD25(-) T cells from zymosan-treated mice. These results show that innate immune response through TLR2 and dectin 1 results in suppressor cytokine production by APCs and promotes the regulatory function of T cells. Our study demonstrates the possible involvement of signaling through innate immune receptors such as TLR2 and dectin 1 in reduced T1D incidence under the conditions of low hygiene, and the potential of targeting them for treating T1D.
 ...
PMID:Induction of innate immune response through TLR2 and dectin 1 prevents type 1 diabetes. 1905 Feb 49

Toll-like receptors (TLRs) and the innate immune system play a key role in sensing and eliminating microbial infections. Interactions between TLRs and their ligands expressed by microbial pathogens induce a cascade of intracellular signaling events, culminating in the upregulation of proinflammatory pathways. Over the past two decades, numerous studies have established the role of the acquired immune system in the mechanism triggering type 1 diabetes (T1D). The recent discovery of TLRs has led to the recognition that the innate immune system may act, under some circumstances, as a double-edged sword. In addition to its beneficial role in host defense, it may lead to upregulation of proinflammatory autoimmune responses, islet destruction and diabetes. Indeed, recent observations are consistent with the hypothesis that altered innate functions exist in patients with T1D and could be part of the mechanism leading to disease onset, but the underlying mechanisms and the relevance of these alterations to early events triggering disease remain to be identified. Data obtained from mouse and rat models of T1D implicated TLR pathways in both disease induction and prevention. In both the NOD mouse and diabetes-prone BB (BBDP) rat, TLR upregulation can suppress disease. In the BioBreeding Diabetes Resistant (BBDR) rat, however, diabetes induced by virus infection involves the upregulation of TLR9 pathways, and generic TLR upregulation synergizes with virus infection on diabetes induction. Studies performed in mouse models of T1D with spontaneous or induced T1D implicate TLR1, TLR2, TLR3, and TLR7 in disease mechanisms. The finding that TLR pathways are involved in mediating islet inflammation holds great promise for identifying new molecules that could potentially be targeted to specifically suppress the autoimmune process in individuals at high risk for disease development. The potential link between TLR upregulation and autoimmunity emphasizes the need for caution in using new therapies involving TLR agonists as vaccine adjuvants.
 ...
PMID:The role of Toll-like receptor pathways in the mechanism of type 1 diabetes. 1919 42


1 2 3 4 5 6 7 Next >>