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At least 793 records · Page 44Linked to original sources
PubMed2004

Expression of functional toll-like receptor-2 and -4 on alveolar epithelial cells.

The recognition of potentially harmful microorganisms involves the specific recognition of pathogen-associated molecular patterns (PAMPs) and the family of Toll-like receptors (TLRs) is known to play a central role in this process. TLR-4 is the major recognition receptor for lipopolysaccharide (LPS), a component of gram-negative bacterial cell walls, whereas TLR-2 responds to bacterial products from gram-positive organisms. Although resident alveolar macrophages are the first line of defense against microbial attack, it is now understood that the alveolar epithelium also plays a pivotal role in the innate immunity of the lung. The purpose of the current study was to determine whether human primary type II alveolar epithelial cells (ATII) express functional TLR-2 and TLR-4 and how they may be regulated by inflammatory mediators. We have used reverse transcriptase-polymerase chain reaction and flow cytometry to determine basal and inducible expression on ATII. We have used highly purified preparations of the gram-positive bacterial product lipoteichoic acid (LTA) and LPS to look at the functional consequences of TLR-2 and TLR-4 ligation, respectively, in terms of interleukin-8 release. We have shown that human primary ATII cells express mRNA and protein for both TLR-2 and TLR-4, which can be modulated by incubation with LPS and tumor necrosis factor. Furthermore, we have demonstrated that these receptors are functional. This suggests that ATII have the potential to contribute significantly to the host defense of the human alveolus against bacteria.

Base Sequence↗
PubMed2006

Mannose binding lectin and soluble Toll-like receptor 2 in heart failure following acute myocardial infarction.

BACKGROUND: To determine the relationship between markers of innate immunity and clinical outcomes in patients with heart failure (HF) after acute myocardial infarction (AMI). Atherogenesis and HF is associated with the altered control of inflammation by innate immune defenses that include pattern-recognition molecules such as Toll-like receptors (TLRs) and mannose-binding lectin (MBL). METHODS AND RESULTS: We assessed circulating levels, and relationships with adverse outcomes of MBL and sTLR2 levels in 234 patients with AMI complicated with HF. Blood was sampled at baseline (median 3 days after AMI), 1 month, 1 year, and 2 years. For comparison, we also measured MBL and sTLR2 levels in 20 age- and sex-matched healthy controls. Patients with post-MI HF had markedly decreased serum levels of sTLR2 at baseline that increased during follow-up, but did not reach the concentrations present in healthy controls. In contrast, serum MBL levels were initially normal in patients with post-MI HF, but decreased during follow-up, and MBL levels measured 1 month after the index infarct were inversely associated with a higher incidence of reinfarction. CONCLUSION: These findings suggest that circulating levels of MBL and sTLR2 may reflect different aspects of the innate immune response and further suggest the involvement of innate immunity responses in the pathogenesis of post-MI HF.

Aged↗
PubMed2003

Discrimination of single bars by the honeybee (Apis mellifera).

The bees learn to come for a reward to a very simple pattern, a black bar in a fixed position on a white background, in a Y-choice apparatus, with the targets presented in the vertical plane at a fixed range. They were trained on a number of different arrangements of a single bar on one or both targets. The trained bees were then given appropriate tests to discover what cues they had learned. A cue is an essential parameter that is recognized, not the whole pattern. At the choice point they learn exactly which way to look for consistent cues. After training on a single broad bar versus a blank target, they respond in tests to any area of black where they expect to see it, and are less able to detect it the more it has been displaced from the training position. They are more sensitive to vertical than to horizontal displacement of the bar. The cue is anything black of the right size. They do not recognize the shape or orientation of the bar. When trained to discriminate between two bars at right angles to each other, centred on the reward hole, the cue is the edge orientation at the expected places on the targets, and the bees are less able to discriminate the orientation cues the more they are displaced. When trained on a pair of broad black bars in different positions, the cues are the vertical positions of the centres. Division of the bar into squares, or making the edges stepped, removes the orientation cue but not the position cue. Addition of a large black spot or a checkerboard background to the original bar prevents discrimination, as if the spatial reference frame is disturbed. In training, or testing trained bees, parallax does not assist the discrimination of orientation.

Animals↗
PubMed2006

Exploitation of the Toll-like receptor system in cancer: a doubled-edged sword?

The toll-like receptor (TLR) system constitutes a pylogenetically ancient, evolutionary conserved, archetypal pattern recognition system, which underpins pathogen recognition by and activation of the immune system. Toll-like receptor agonists have long been used as immunoadjuvants in anti cancer immunotherapy. However, TLRs are increasingly implicated in human disease pathogenesis and an expanding body of both clinical and experimental evidence suggests that the neoplastic process may subvert TLR signalling pathways to advance cancer progression. Recent discoveries in the TLR system open a multitude of potential therapeutic avenues. Extrapolation of such TLR system manipulations to a clinical oncological setting demands care to prevent potentially deleterious activation of TLR-mediated survival pathways. Thus, the TLR system is a double-edge sword, which needs to be carefully wielded in the setting of neoplastic disease.

Disease Progression↗
PubMed2003

Nods, Nalps and Naip: intracellular regulators of bacterial-induced inflammation.

The innate immune system is the most ancestral and ubiquitous system of defence against microbial infection. The microbial sensing proteins involved in innate immunity recognize conserved and often structural components of microorganisms. One class of these pattern-recognition molecules, the Toll-like receptors (TLRs), are involved in detection of microbes in the extracellular compartment whereas a newly discovered family of proteins, the NBS-LRR proteins (for nucleotide-binding site and leucine-rich repeat), are involved in intracellular recognition of microbes and their products. NBS-LRR proteins are characterized by three structural domains: a C-terminal leucine-rich repeat (LRR) domain able to sense a microbial motif, an intermediary nucleotide binding site (NBS) essential for the oligomerization of the molecule that is necessary for the signal transduction induced by different N-terminal effector motifs, such as a pyrin domain (PYD), a caspase-activating and recruitment domain (CARD) or a baculovirus inhibitor of apoptosis protein repeat (BIR) domain. Two of these family members, Nod1 and Nod2, play a role in the regulation of pro-inflammatory pathways through NF-kappaB induced by bacterial ligands. Recently, it was shown that Nod2 recognizes a specific peptidoglycan motif from bacteria, muramyl dipeptide (MDP). A surprising number of human genetic disorders have been linked to NBS-LRR proteins. For example, mutations in Nod2, which render the molecule insensitive to MDP and unable to induce NF-kappaB activation when stimulated, are associated with susceptibility to a chronic intestinal inflammatory disorder, Crohn's disease. Conversely, mutations in the NBS region of Nod2 induce a constitutive activation of NF-kappaB and are responsible for Blau syndrome, another auto-inflammatory disease. Nalp3, which is an NBS-LRR protein with an N-terminal Pyrin domain, is also implicated in rare auto-inflammatory disorders. In conclusion, NBS-LRR molecules appear as a new family of intracellular receptors of innate immunity able to detect specific bacterial compounds and induce inflammatory response; the dysregulation of these processes due to mutations in the genes encoding these proteins is involved in numerous auto-inflammatory disorders.

Adaptor Proteins, Signal Transducing↗
PubMed1986

The diving response in man: effects on sympathetic activity in muscle and skin nerve fascicles.

Multi-unit recordings of muscle-nerve sympathetic activity (m.s.a) or skin-nerve sympathetic activity (s.s.a) were made in the left peroneal nerve of sixteen healthy volunteers during simulated diving by immersion of the face in a tub of water. The procedure was varied by the use of different water temperatures, by diving with snorkel breathing, by apnoea without diving, and by apnoea with a stream of air against the face instead of immersion in water. Diving for 12 s elicited a pronounced activation of m.s.a., the mean increase from control periods being 360%. The response was stronger with lower water temperatures. Immersion of the whole face evoked a stronger increase in m.s.a. than immersion of mouth and nose only. Diving without apnoea elicited a significant but weaker increase in m.s.a., whereas apnoea only for 12 s did not influence the sympathetic outflow. Cool air against the face during apnoea for 12 s was associated with a significant increase in m.s.a. The increase in m.s.a. usually occurred before the bradycardia. On emersion, m.s.a. ceased abruptly, whereas the bradycardia persisted for a few seconds. Mental arithmetic during diving did not change the m.s.a. response but reduced the bradycardia. M.s.a. increased despite increasing blood pressure levels. On emersion, m.s.a. did not reappear until the pre-diving blood pressure level was attained. S.s.a was inhibited on diving, with concomitant vasodilatation in the skin as recorded in the big toe. It is concluded that the response of m.s.a. to diving is initiated by a central 'pattern recognition' of an input from facial receptors, that this input and the effects of apnoea, acting by mutual reinforcement, maintain the strong sympathetic outflow, and that the mechanism releasing m.s.a. on diving overrides the normal blood pressure regulatory function of m.s.a. Diving exerts differentiated influence on different parts of the sympathetic nervous system, as illustrated by the inhibition of s.s.a.

Adult↗
PubMed1993

Responses of the starburst amacrine cells to moving stimuli.

1. Rabbit retinas were isolated from the eye and incubated in the presence of 3H-choline. Samples of retina taken from a defined midperipheral eccentricity were spread over the domed end of a fiberoptic bundle that formed the floor of a superfusion chamber. The rate of release of labeled acetylcholine by the starburst amacrine cells was studied. 2. When the retina was stimulated by moving gratings, the cells vigorously increased their secretion of acetylcholine. Responses were observed when the bars were as small as 60 microns in width. Systematically varying the spatial and temporal frequency of stimulation revealed that temporal frequency was the dominant variable: the cells responded best to stimuli of 1-4 Hz, whether those stimuli were flashing lights, fine gratings moving slowly, or coarse gratings moving rapidly. 3. With temporal frequency constant, the cells' responses decreased as the spatial frequency of the grating increased. The decreased response to fine gratings is most likely due, at least in part, to lateral interactions that become stronger as the light and dark bars become more closely spaced. These could occur in either the outer or inner retina. 4. The velocity tuning curve for the starburst cells' release of acetylcholine matched fairly well the velocity tuning of ON-OFF directionally selective cells in the rabbit. It did not correspond at all well with the tuning curve for the ON directionally selective cells. If the ON cells receive input from the starburst cells, that input appears to be quite indirect.(ABSTRACT TRUNCATED AT 400 WORDS)

Acceleration↗
PubMed2005

[Role of cytokines and pathogen associated molecular pattern receptors in sepsis].

Sepsis is life-treating state caused by overwhelming inflammatory response to infection accompanied by disregulation of non-specific immunity mechanisms. In this review we discussed influence of Gram-positive and Gram-negative bacterial virulence factors, cytokines as well as pathogen associated molecular pattern receptors (TLR-toll like receptors, peptydoglican recognition proteins, nucleotide binding oligomerization domains, triggering receptor expressed on myeloid cells-1) on the development and course of sepsis.

Gram-Negative Bacterial Infections↗
PubMed1990

Long-term effects of cholinergic agonists on memory.

Animal models provide important information about strategies that can be used to assess the effects of chronic exposure to drugs or other compounds. Furthermore, when used in conjunction with analyses designed to utilize the many advantages of animal models to examine learning and memory, these kinds of experiments can have significant ramifications for assessing the mnemonic effects of chronic drug use in people. Finally, given that aging is accompanied by significant deterioration of neurochemical systems, which may compromise the functions of those systems, the results from the experiments with DFP predict that changes in learning and memory abilities that are not apparent in young individuals may begin to surface as those individuals age or may appear following any other kind of insult to their nervous system.

Animals↗
PubMed1996

The NMDA and GABA-A receptors in behavioral activity of rats.

The effects of bicuculline (0.25 mg/kg ip) and AP-7 (5 nmols icv) on the processes of retrieval, consolidation of conditioned reflexes, object recognition and locomotor activity were tested in rats. AP-7, bicuculline and AP-7 with bicuculline increased (but not significantly) locomotor and exploratory activity in the open field test. Only coadministration of AP-7 with bicuculline facilitated retrieval of passive avoidance in rats, but was without effect on consolidation in this test. AP-7 or bicuculline also did not influence on consolidation, when they were given alone. Object recognition was impaired (but not significantly) in groups of rats treated with bicuculline and bicuculline with AP-7.

2-Amino-5-phosphonovalerate↗
PubMedDate not supplied

Effects of pharmacologically induced changes in NMDA-receptor activity on long-term memory in humans.

In a double-blind crossover design, either 30 mg of the noncompetitive NMDA-receptor antagonist memantine or a placebo was administered to 40 healthy male volunteers. Twenty line drawings of objects and 20 photographs of unfamiliar faces were presented on a computer screen. After a retention interval of 80 min, the participants' task was to select the original objects and faces from a set of 80 items. Results were analyzed applying a signal-detection-theory approach. Recognition performance for objects was significantly impaired under memantine as compared to placebo, whereas performance on face recognition was not affected. Findings support the notion of differential effects of NMDA-receptor antagonists on memory functions in humans.

Adult↗
PubMed1998

Spatiotemporal patterns at the retinal output.

Edge enhancement in the retina is thought to be mediated by classical center-surround antagonism, first encountered as the interactions between horizontal cells and cones. But in the salamander retina these interactions do little to enhance edges. Instead, a robust dynamic interaction between amacrine and bipolar cells appears to be responsible for a sharp edge enhancement. To demonstrate this we recorded extracellularly from a single ganglion cell and moved a flashed square, 300 micro(m) on a side, over a 1.5 x 1.0 mm2 grid at 25-micro(m) increments. Playing back all of these recordings simultaneously simulated the pattern of responses that would have been measured from an array of ganglion cells. The emerging pattern of ganglion cell activity first faithfully represented the flashed square, but after approximately 60 ms the center of the representation collapsed, leaving a representation of only the edges. We inferred that the feedback synapse from amacrine to bipolar cells at gamma-aminobutyric acid-C (GABAC) receptors mediated this effect: bicuculline and strychnine were ineffective in altering the response pattern, but in picrotoxin the center of the representation did not collapse. The GABAergic amacrine cells thought to mediate this effect have quite narrow spread of processes, so the existence of this edge-enhancing effect suggests a mechanism quite different from classical lateral inhibition, namely the delayed inhibition of a spatially expanding input pattern.

Ambystoma↗
PubMed2002

Chemokines, innate and adaptive immunity, and respiratory disease.

Selective leukocyte trafficking and recruitment is primarily regulated by a specific family of small proteins called "chemokines". This extended family shepherds and guides leukocytes through their lives, facilitating their development, regulating their interactions with other leukocyte types, and guiding their recruitment to sites of inflammation. Through the actions of chemokines, allergen sensitization is regulated in atopic asthma, through the controlled migration of dendritic cells, T- and B-lymphocytes, mast cells and basophils. Subsequently, atopic inflammation is driven by chemokine-directed recruitment of eosinophils, basophils and lymphocytes. Diseases from cancer to chronic obstructive pulmonary disease to interstitial fibrosis are all potential targets for chemokine receptor antagonism. Innate immunity (the early pattern-recognition responses to stimuli such as lipopolysaccharide, viral proteins and bacterial DNA) needs to bridge the gap to specific immunity and antibody production and immunological memory. Again, chemokines are likely to be fundamental mediators of these responses. Chemokines are fundamental regulators of leukocyte homeostasis and inflammation, and their antagonism by small molecule chemokine receptor antagonists may be of enormous importance in the future treatment of human respiratory disease.

Animals↗
PubMed2005

Monocyte toll-like receptor 4 expression and LPS-induced cytokine production increase during gestational aging.

Premature newborns are highly susceptible to severe bacterial infections. This is partially due to their immature innate immune system, characterized by decreased neutrophil and monocyte activity as well as by reduced concentrations of complement factors. However, additional mechanisms might be important for innate immunity and are still the subject of considerable debate. The importance of pattern recognition domains such as Toll-like receptors (TLR) has been fully acknowledged within the last few years. Therefore, we investigated age-related monocyte TLR4 expression and lipopolysaccharide-induced cytokine secretion from very low birth weight infants (VLBWI) and from newborns after wk 30 of gestation in comparison to healthy adults. In VLBWI, expression of TLR4 surface protein, detected by flow cytometry, and TLR4-specific mRNA, quantified by real time-PCR, were significantly reduced in comparison to mature infants and to adults. Reduced TLR4 expression was paralleled by significantly diminished ex vivo LPS stimulated IL-1beta, IL-6, and tumor necrosis factor-alpha secretion into whole blood. We conclude that, in VLBWI, the minimized expression of TLR4 contributes to the susceptibility of VLBWI to infections with Gram-negative bacteria due to the lack of cytokines to boost initial immune response.

Cytokines↗
PubMed2000

The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors.

Toll-like receptors (TLRs) have been shown to participate in the recognition of pathogens by the innate immune system, but it is not clear how a restricted family of receptors has the capacity to recognize the wide spectrum of TLR stimuli known to exist. We report here that two members of the TLR family, TLR2 and TLR6, together coordinate macrophage activation by Gram-positive bacteria and the yeast cell-wall particle, zymosan. TLR6 and TLR2 both are recruited to the macrophage phagosome, where they recognize peptidoglycan, a Gram-positive pathogen component. By contrast, TLR2 recognizes another component, bacterial lipopeptide, without TLR6. The requirement for TLR cooperation is supported by the finding that TLR2 needs a partner to activate tumor necrosis factor-alpha production in macrophages. Dimerization of the cytoplasmic domain of TLR2 does not induce tumor necrosis factor-alpha production in macrophages, whereas similar dimerization of the TLR4 cytoplasmic domain does. We show that the cytoplasmic domain of TLR2 can form functional pairs with TLR6 or TLR1, and this interaction leads to cytokine induction. Thus, the cytoplasmic tails of TLRs are not functionally equivalent, with certain TLRs requiring assembly into heteromeric complexes, whereas others are active as homomeric complexes. Finally, we show that TLR6, TLR2, and TLR1 are recruited to macrophage phagosomes that contain IgG-coated erythrocytes that do not display microbial components. The data suggest that TLRs sample the contents of the phagosome independent of the nature of the contents, and can establish a combinatorial repertoire to discriminate among the large number of pathogen-associated molecular patterns found in nature.

Animals↗
PubMed1990

Differential ontogenic development of three receptors comprising the NMDA receptor/channel complex in the rat hippocampus.

The postnatal development of the three receptor binding sites that constitute the N-methyl-D-aspartate (NMDA) receptor channel/complex was examined in six hippocampal regions of rats using quantitative receptor autoradiography. NMDA-sensitive [3H]-glutamate binding, strychnine-insensitive [3H]glycine binding, and [3H]N-(1-[2-thienyl]cyclohexyl)-3,4-piperidine [( 3H]TCP) binding were measured to examine the ontogeny of NMDA recognition sites, glycine modulatory sites, and PCP receptors, respectively. NMDA-sensitive [3H]glutamate binding transiently exceeded adult levels by 50 to 120% in all regions examined, with peak densities generally occurring between postnatal days (PND) 10 and 28. Stratum radiatum CA1 binding increased slowly from 49 to 61% of the adult value between PND 1 and 7, after which, binding rapidly rose to 151% of adult values at PND 14, remained elevated through PND 28, and then decreased to adult levels. The ontogenic profile of NMDA recognition site binding was similar in other hippocampal regions, although the initial age of maximal binding and the period of stabilization varied. The ontogenic profiles of glycine modulatory site binding and PCP receptor binding were very similar to each other. Development was delayed, however, with respect to NMDA recognition site binding. The rapid development of binding observed between PND 7 and 14 with NMDA receptors in stratum radiatum CA1 was contrasted by a much slower increase in glycine and PCP receptor binding. Furthermore, maximal glycine and PCP receptor binding densities were not reached until PND 28 and were lower than NMDA recognition site binding densities. The observed developmental patterns of binding to each of the receptor components of the NMDA receptor channel/complex are consistent with postnatal changes in cytoarchitecture, synaptogenesis, afferent lamination, and functional development of the hippocampus. However, the relative overexpression of NMDA recognition sites with respect to glycine and PCP receptors between PND 7 and 21 suggests that there is differential expression of these binding sites during development.

Animals↗
PubMed1992

Iron uptake and molecular recognition in Pseudomonas putida: receptor mapping with ferrichrome and its biomimetic analogs.

The presence of an Fe(3+)-ferrichrome uptake system in fluorescent Pseudomonas spp. was demonstrated, and its structural requirements were mapped in Pseudomonas putida with the help of biomimetic ferrichrome analogs. Growth tests, 55Fe3+ uptake, and competition experiments demonstrated that the synthetic L-alanine derivative B5 inhibits the action of ferrichrome but does not facilitate Fe3+ transport, while the enantiomeric D-Ala derivative B6 fails to compete with ferrichrome. Contraction of the molecule's envelope by replacing L-Ala by glycine provided a synthetic carrier, B9, which fully simulates ferrichrome as a growth promoter. Sodium azide inhibited 55Fe3+ uptake of the Gly derivative B9, suggesting an active transport process. These data demonstrate the chiral discrimination of the ferrichrome receptor and its sensitivity to subtle structural changes. They further confirm that receptor binding is a necessary but not sufficient condition for Fe3+ uptake to occur and suggest that binding to the receptor and transport proteins might rely on different recognition patterns.

Bacterial Outer Membrane Proteins↗