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Results for “Receptors, Pattern Recognition”

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PubMed2004

CD14 and toll-like receptor 4: a link between infection and acute coronary events?

The CD14 receptor is a pattern recognition molecule in the innate immune response against microorganisms and other exogenous and endogenous stress factors. The most important CD14 signalling co-receptor is toll-like receptor 4 (TLR4), which activates, among others, the nuclear factor kappaB (NF-kappaB) inflammatory pathway. Besides its role in innate immunity and host defence, the proinflammatory cytokines expressed upon TLR4/NF-kappaB pathway activation exert proatherogenic effects. The CD14 C(-260)T promoter and TLR4 Asp299Gly functional polymorphisms have been recently implicated in the development of cardiovascular events, suggesting that the genetically determined inflammatory response against pathogens or their antigens may have a major role in atherogenesis and subsequent acute events. Is the association of these polymorphisms with cardiovascular disease more evidence for the implication of infection, especially by Gram negative bacteria, in the development of acute coronary events? This article reviews the molecular basis, biological functions, and clinical implications of the CD14/TLR4 polymorphisms in the development of cardiovascular events.

Cell Communication↗

PubMed2002

Pulmonary innate immune proteins and receptors that interact with gram-positive bacterial ligands.

The two major gram-positive bacterial (GPB) ligands are peptidoglycan (PGN) and lipoteichoic acid (LTA). These polymeric LTA and highly organized PGN contain repeating carbohydrate moieties, which are potential targets for pattern recognition molecules. The major pattern recognition proteins and receptors, which bind GPB, either have a lectin, PGN recognition, collagen or leucine-rich repeat (LRR) domain. The soluble innate immune proteins (IIPs) that bind to PGN and LTA include pulmonary collectins surfactant-associated proteins (SP-) A and D, lectin-like pentraxins C-reactive protein (CRP) and serum amyloid P component (SAP), and sCD14. Membrane-anchored lectin or lectin-like group members include macrophage mannose receptor (MR), complement receptor 3 (CR3, or Mac-1, or integrin CD11b/CD18), scavenger receptor A (SRCL-1), lectin-like oxidized LDL receptor 1 (LOX-1), and GPI-anchored CD14. Although Toll-like receptor (TLR) 2 and 4, and CD14 contain extracellular LRR domains, only TLRs have a cytoplasmic domain for signal transduction. Three of the four recently discovered human PGN recognition proteins (PGRP) have a transmembrane domain, and hence, considered as true receptors for GPB. Since lysozyme is the only known pulmonary enzyme that can lyse bacterial cell wall PGN, other innate immune molecules appear to be responsible for signalling and enhancing the clearance of GPB infection from the lung. Interestingly, pulmonary collectins bind not only to GPB ligands but also to the receptors, CD14 and TLR, and antigen processing cells such as dentritic cells. These complex interactions appear to play major roles in linking innate and adaptive immunity, and maintaining a pathogen-free lung with minimal, or no inflammation.

Animals↗

PubMed2000

Molecular events of bacterial-induced maturation of dendritic cells.

In order to protect the body from infectious microorganisms, mammals have developed powerful lines of defense, consisting in innate and adaptive immune responses. The innate response is phylogenetically more ancient and, for a long time, it has been considered to be broadly directed to microorganisms. However, the discovery of a new class of receptors, involved in recognition of patterns characteristic of groups of microorganisms (the toll-like receptor family) has re-evaluated the role of the innate immune system as a discriminating system. Indeed, there is increasing evidence that the induction of different types of effector adaptive responses are directed by the innate immune system after recognition of particular groups of pathogens. The central role of Dendritic cells (DC) in the induction of adaptive immune responses towards infectious agents has been extensively described, but, recently, a new role of DC as a link between the non-antigen- and the antigen-specific responses has been proposed. DC have, indeed, the capacity to recruit and activate cells of the innate immune system upon inflammation. Thus. understanding the interaction of bacteria with DC, and the early molecular events resulting from this interaction may shed some light on the mechanisms of initiation of the immune response to infectious agents and on aspects of invasiveness, pathogenicity, and the persistence of certain bacteria.

Animals↗

PubMed2001

Drosophila Toll is activated by Gram-positive bacteria through a circulating peptidoglycan recognition protein.

Microbial infection activates two distinct intracellular signalling cascades in the immune-responsive fat body of Drosophila. Gram-positive bacteria and fungi predominantly induce the Toll signalling pathway, whereas Gram-negative bacteria activate the Imd pathway. Loss-of-function mutants in either pathway reduce the resistance to corresponding infections. Genetic screens have identified a range of genes involved in these intracellular signalling cascades, but how they are activated by microbial infection is largely unknown. Activation of the transmembrane receptor Toll requires a proteolytically cleaved form of an extracellular cytokine-like polypeptide, Spätzle, suggesting that Toll does not itself function as a bona fide recognition receptor of microbial patterns. This is in apparent contrast with the mammalian Toll-like receptors and raises the question of which host molecules actually recognize microbial patterns to activate Toll through Spätzle. Here we present a mutation that blocks Toll activation by Gram-positive bacteria and significantly decreases resistance to this type of infection. The mutation semmelweis (seml) inactivates the gene encoding a peptidoglycan recognition protein (PGRP-SA). Interestingly, seml does not affect Toll activation by fungal infection, indicating the existence of a distinct recognition system for fungi to activate the Toll pathway.

Amino Acid Sequence↗

PubMed2004

Toll-like receptors 2 and 4, and acute phase cytokine gene expression in dexamethasone and growth hormone treated dairy calves.

Cattle are exposed to growth hormone stimulants and to stressors that cause cortisol release. Both of these hormones affect immune responses which may reduce disease resistance. Toll-like receptors are the pattern recognition molecules of pathogens that are on immune cells. They then orchestrate the induction of the appropriate acute phase cytokines of the early innate response. The objective of this study was to determine changes in toll-like receptors and acute phase cytokines following treatment with a synthetic glucocorticoid (dexamethasone) and growth hormone (GH). Twenty-eight calves were given the control (Cnt), dexamethasone (DEX), GH, or dexamethasone and GH (Both) treatments from 3 until 56 days of age. Blood was collected by jugular venipuncture on days 14, 28, 42, and 56. On day 56, a lung lavage was performed and spleen and thymus tissues collected. Total RNA was extracted from blood leukocytes, lung lavage cells, spleen and thymus cells. Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) was used to quantify interleukin-1 (IL-1), IL-1 receptor antagonist (IL-1Ra), tumor necrosis factor (TNF)-alpha, toll-like receptor 2 (TLR2), and toll-like receptor 4 (TLR4). Blood leukocytes had a time effect for IL-1Ra (P < 0.01), with a trend for a treatment effect (P = 0.07) and had a treatment by time interaction (P < 0.05). IL-1, TNF, and TLR2 and TLR4 were greatest (P < 0.05) for Cnt only at day 14. IL-1 expression of lung lavage cells was greatest (P < 0.05) for calves on the Both treatment compared to the other three treatments. However, IL-1Ra was not different among the treatments. Toll-like receptor 2 expression was enhanced with Both compared to either DEX (P < 0.05) or GH (P < 0.05) and tended to be greater than Cnt expression (P = 0.07). Expression of TLR4 tended to be reduced by Both compared to Cnt (P = 0.06). Tumor necrosis factor-alpha was greatly enhanced by Both compared to the other three treatments (P < 0.05). Spleen cell tended to have different IL-1 expression between GH and Both (P < 0.10). Interleukin-1 receptor antagonist and TLR2 and TLR4 were not different among treatments. However, TNF-alpha expression was enhanced by the DEX treatment alone compared to the GH treatment (P < 0.05), and tended (P < 0.10) to be greater than Cnt expression. None of the gene expressions were different among treatments for thymus cells. Lung lavage cell expression appears to be most susceptible to these hormones while blood leukocyte expression was only slightly affected, and thymus cells were not affected at all. These data demonstrate that TLR2 and TLR4 and acute phase cytokine expression can be altered by stress and growth hormones, which may decrease resistance of those animals to disease.

Animals↗

PubMed2002

Generation of mice deficient for macrophage galactose- and N-acetylgalactosamine-specific lectin: limited role in lymphoid and erythroid homeostasis and evidence for multiple lectins.

Macrophage receptors function in pattern recognition for the induction of innate immunity, in cellular communication to mediate the regulation of adaptive immune responses, and in the clearance of some glycosylated cells or glycoproteins from the circulation. They also function in homeostasis by initiating the engulfment of apoptotic cells. Evidence has suggested that macrophage receptors function to recognize cells that are destined for programmed cell death but not yet overtly apoptotic. We have examined the function of a macrophage receptor specific for unsialylated glycoproteins, known as the mouse macrophage galactose- and N-acetylgalactosamine-specific lectin (mMGL) (Ii et al., J. Biol. Chem. 265:11295-11298, 1990; Sato et al., J. Biochem. [Tokyo] 111:331-336, 1992; Yamamoto et al., Biochemistry 33:8159-8166, 1994). With targeted disruption, we tested whether mMGL is necessary for macrophage function, controlled thymic development, the loss of activated CD8 T cells, and the turnover of red blood cells. Evidence indicates that mMGL may play a nonessential role in several of these macrophage functions. Experiments are presented that indicate the existence of another galactose- and N-acetylgalactosamine-recognizing lectin distinct from mMGL. This may explain the absence of a strong phenotype in mMGL-deficient mice.

Animals↗

PubMed2005

Opioid receptor-like 1 (ORL1) molecular "road map" to understanding ligand interaction and selectivity.

The opioid receptor-like 1 (ORL1) system has attracted a lot of attention owing to its diverse physiological role and by its close structural proximity toward the classical opioid receptors. Even though they share a close sequence similarity, the ligand recognition pattern for the ORL1 receptor and the classical opioid receptors remains highly distinct. In addition, functional diversification observed between the ORL1 receptor system and classical opioid receptors clearly indicates that subtle changes in the structural makeup of a receptor are enough to delineate them. A clear understanding of the structural requirements for ligand selectivity by classical opioid receptors and identification of a common "opioid binding pocket" has not been achieved yet. At this juncture, the ORL1 receptor system presents itself as a potential tool in the quest for elucidating critical elements directing ligand selectivity. The current paper is a compilation of several site-directed mutagenesis studies conducted on the ORL1 receptor system. The mutagenesis studies concentrated on the transmembrane domain residues are reported with the changes observed in terms of both binding and functional activation of the receptor. Given the critical role played by this G-protein coupled receptor, molecular level understanding of this ORL1 receptor system would aid in rational design and development of agonists and antagonists with multiple therapeutic applications.

Amino Acids↗

PubMedDate not supplied

Toll like receptors and viruses.

Toll like receptors (TLRs) are 'pattern recognition proteins' that discriminate between self and non-self. They interact with products of infectious agents to activate cells of the innate immune system and also stimulate the adaptive immune system. Intracellular and extracellular TLRs recognise a wide range of viruses leading to the production of different cytokines. In this paper, we summarise the types of TLRs that recognise viruses, the cytokines produced, the specific cell types involved and the activation pathways that have been characterised. We also provide an overview of the viruses demonstrated to interact with TLRs. A greater understanding of relationships between viruses or viral products and TLRs should improve understanding of pathogenesis and lead to the development of new anti-viral therapies.

Animals↗

PubMed2005

Differential gene expression of IGF-I, IGF-II, and toll-like receptors 3 and 5 during embryogenesis in hybrid (channel x blue) and channel catfish.

Insulin-like growth factors-I and-II (IGF-I and IGF-II) play important roles in growth and development of mammals. Toll-like receptors (TLRs) are pattern recognition molecules that orchestrate the induction of early innate immune response by recognition of specific sequences. Evidence is growing that suggests a relationship between growth and immune function. The objective of the study was to examine changes in gene expression of IGF-I, IGF-II, TLR3, and TLR5 during embryogenesis and early larval development in hybrid (channel catfishxblue catfish) and channel catfish. Egg samples were taken pre- and post-fertilization; embryos were collected at two stages of embryogenesis, at hatch, and at swim-up. All genes were detected in unfertilized catfish eggs. Expression levels of TLR5 and IGF-I mRNA in channel catfish and expression levels of TLR3, IGF-I, and IGF-II mRNA in hybrids increased over time (P<0.01). Effect of time was not significant for expression of IGF-II or TLR3 mRNA in channel catfish and for TLR5 mRNA in hybrid catfish. Results of this study suggest growth (IGF-I and IGF-II) and immune (TLR3 and TLR5) associated genes could be functional and play important roles during embryogenesis and early development of hybrid and channel catfish.

Animals↗

PubMed2003

Toll-like receptor 4 plays no role in susceptibility of mice to Mycobacterium tuberculosis infection.

Although various members of the pattern recognition Toll-like receptor (TLR) family have been implicated in host resistance to Mycobacterium tuberculosis infection, it remains unclear if the TLR4 receptor plays an important role. We demonstrate here that infection of TRL4-competent and TLR4-deficient mice on the C3H inbred mouse strain background had similar outcomes, measured in terms of the course of the disease, cell accumulation patterns in the lungs, and lung histopathology. These data argue against a significant role for TLR4 in immunity to tuberculosis in the mouse model.

Animals↗

PubMedDate not supplied

GPCR-tailored pharmacophore pattern recognition of small molecular ligands.

The goal of our work was to differentiate between patterns, which are responsible for the activity of small molecular ligands binding to G-protein coupled receptors (GPCRs) and molecules, which are pharmacologically active on other target classes. Second the aim was to go one step further and analyze the chemical space occupied by GPCR active ligands itself, to distinguish between the actives of different subclasses or even cluster ligands for single receptors. To achieve these objectives, we have built a database of small, organic molecules, which bind to GPCRs. Once this crucial foundation for pattern recognition has been laid, we needed to find a descriptor, which is able to detect the compulsory features responsible for activity within a molecule. In this matter we found that the well accepted pharmacophore descriptor served us well. Finally we needed to find a method to display the clustering or separation of the specific ligands. We found that self-organizing maps (SOMs) perform excellently in this task. We herein present the analysis of the chemical space of active compounds, depending on their biological target, the GPCRs. We will also discuss the techniques used to create the chemical spaces. The findings can be applied and have an impact at various stages of the drug discovery process.

Ligands↗

PubMed2002

Dependence of bacterial protein adhesins on toll-like receptors for proinflammatory cytokine induction.

Toll-like receptors (TLRs) are important signal transducers that mediate inflammatory reactions induced by microbes through pattern recognition of virulence molecules such as lipopolysaccharide (LPS) and lipoproteins. We investigated whether proinflammatory cytokine responses induced by certain bacterial protein adhesins may also depend on TLRs. In differentiated THP-1 mononuclear cells stimulated by LPS-free recombinant fimbrillin (rFimA) from Porphyromonas gingivalis, cytokine release was abrogated by monoclonal antibodies (MAbs) to CD14 and TLR4 but not to TLR2. Similar experiments using anti-beta2 integrin MAbs suggested that beta2 integrins (CD11/CD18) also play a role in cytokine induction by rFimA or native fimbriae. Minor fimbriae (distinct from the fimA-encoded major fimbriae) of P. gingivalis induced proinflammatory cytokine release in a CD14- and TLR2-dependent mode. Cytokine induction by BspA, a leucine-rich repeat protein from Bacteroides forsythus, depended heavily on CD14 and TLR2. We also found that the ability of the streptococcal protein AgI/II to stimulate cytokine release depended partially on CD14 and TLR4, and the AgI/II segment that possibly interacts with these receptors was identified as its N-terminal saliva-binding region. When THP-1 cells were exposed to rFimA for 24 h, surface expression of CD14 and CD18 was decreased and the cells became hyporesponsive to cytokine induction by a second challenge with rFimA. However, tolerance induction was abolished when the THP-1 cells were pretreated with rFimA in the presence of either anti-CD14 MAb or anti-TLR4 MAb. Induction of cross-tolerance between rFimA and LPS correlated with downregulation of the pattern recognition receptors involved. Our data suggest that the CD14-TLR2/4 system is involved in cytokine production and tolerance induction upon interaction with certain proinflammatory bacterial protein adhesins.

Adhesins, Bacterial↗

PubMed2005

Innate autoimmunity.

The adaptive immune system has evolved highly specific pattern recognition proteins and receptors that, when triggered, provide a first line of host defense against pathogens. Studies reveal that these innate recognition proteins are also self-reactive and can initiate inflammation against self-tissues in a similar manner as with pathogens. This specific event is referred to as "innate autoimmunity." In this review, we describe two classes of autoimmune responses, that is, reperfusion injury and fetal loss syndrome, in which the recognition and injury are mediated by innate immunity. Both disorders are common and are clinically important. Reperfusion injury (RI) represents an acute inflammatory response after a reversible ischemic event and subsequent restoration of blood flow. Findings that injury is IgM and complement dependent and that a single natural antibody prepared from a panel of B-1 cell hybridomas can restore injury in antibody-deficient mice suggest that RI is an autoimmune-type disorder. Fetal loss syndrome is also an antibody- and complement-dependent disorder. Although both immune and natural antibodies are likely involved in recognition of phospholipid self-antigens, inhibition of the complement pathway in rodent models can block fetal loss. As new innate recognition proteins and receptors are identified, it is likely that innate responses to self represent frequent events and possibly underlie many of the known chronic autoimmune disorders normally attributable to dysregulation of adaptive immunity.

Animals↗

PubMed2005

Nod1 participates in the innate immune response to Pseudomonas aeruginosa.

The mammalian innate immune system recognizes pathogen-associated molecular patterns through pathogen recognition receptors. Nod1 has been described recently as a cytosolic receptor that detects specifically diaminopimelate-containing muropeptides from Gram-negative bacteria peptidoglycan. In the present study we investigated the potential role of Nod1 in the innate immune response against the opportunistic pathogen Pseudomonas aeruginosa. We demonstrate that Nod1 detects the P. aeruginosa peptidoglycan leading to NF-kappaB activation and that this activity is diminished in epithelial cells expressing a dominant-negative Nod1 construct or in mouse embryonic fibroblasts from Nod1 knock-out mice infected with P. aeruginosa. Finally, we demonstrate that the cytokine secretion kinetics and bacterial killing are altered in Nod1-deficient cells infected with P. aeruginosa in the early stages of infection.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Divergent synthetic nucleotide motif recognition pattern: design and development of potent immunomodulatory oligodeoxyribonucleotide agents with distinct cytokine induction profiles.

Unmethylated CpG dinucleotides present within certain specific sequence contexts in bacterial and synthetic DNA stimulate innate immune responses and induce cytokine secretion. Recently, we showed that CpG DNAs containing two 5'-ends, immunomers, are more potent in both regards. In this study, we show that an immunomer containing a synthetic CpR motif (R = 2'-deoxy-7-deazaguanosine) is a potent immunostimulatory agent. However, the profile of cytokine induction is different from that with immunomers containing a natural CpG motif. In general, a CpR immunomer induced higher interleukin (IL)-12 and lower IL-6 secretion. Compared with conventional CpG DNAs, both types of immunomers showed a rapid and enhanced activation of the transcription factor NF-kappaB in J774 cells. NF-kappaB activation by CpG DNA corresponded to degradation of IkappaBalpha in J774 cells. All three immunostimulatory oligonucleotides activated the p38 mitogen-activated protein kinase pathway as expected. Immunomers containing CpG and CpR motifs showed potent reversal of the antigen-induced Th2 immune response towards a Th1 type in antigen-sensitized mouse spleen cell cultures. Immunomers containing a CpR motif showed significant antitumor activity in nude mice bearing MCF-7 human breast cancer and U87MG glioblastoma xenografts. These studies suggest the ability for a divergent synthetic nucleotide motif recognition pattern of the receptor involved in the immunostimulatory pathway and the possibility of using synthetic nucleotides to elicit different cytokine response patterns.

Animals↗

PubMed1995

Influence of transmembrane domains on the fusogenic abilities of human and murine leukemia retrovirus envelopes.

The envelopes of two highly divergent oncoviruses, human T-cell leukemia virus type 1 (HTLV-1) and Friend murine leukemia virus (F-MuLV), have distinct patterns of cellular receptor recognition, fusion, and syncytium formation. To analyze the influence of the transmembrane envelope subunit (TM) on fusogenic properties, we substituted either the entire TM or distinct domains from F-MuLV for the corresponding domains in the HTLV-1 envelope. Parental, chimeric, and truncated envelopes cloned into a eukaryotic expression vector were monitored for fusogenic potential in human, rat, and murine indicator cell lines by using a quantitative assay. This highly sensitive assay allowed us to assess the fusogenic properties and syncytium-forming abilities of the HTLV-1 envelope in murine NIH 3T3 cells. All chimeric envelopes containing extracellular sequences of the F-MuLV TM were blocked in their maturation process. Although deletions of the HTLV-1 cytoplasmic domain, alone and in combination with the membrane-spanning domain, did not prevent envelope cell surface expression, they impaired and suppressed fusogenic properties, respectively. In contrast, envelopes carrying substitutions of membrane-spanning and cytoplasmic domains were highly fusogenic. Our results indicate that these two domains in F-MuLV and HTLV-1 constitute structural entities with similar fusogenic properties. However, in the absence of a cytoplasmic domain, the F-MuLV membrane-spanning domain appeared to confer weaker fusogenic properties than the HTLV-1 membrane-spanning domain.

3T3 Cells↗

PubMed2003

High affinity central benzodiazepine receptor ligands. Part 3: insights into the pharmacophore and pattern recognition study of intrinsic activities of pyrazolo[4,3-c]quinolin-3-ones.

Novel 2-phenyl-2,5-dihydropyrazolo[4,3-c]quinolin-3-(3H)-ones (PQs) endowed with high affinity for central benzodiazepine receptor (BzR) were synthesized. In particular, 9-fluoro-2-(2-fluorophenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (2(2)) showed binding affinity in the subnanomolar concentration range and proved to be in vitro a potent antagonist. This finding allowed the nature of the hydrogen bonding receptor site H(2) to be established, as located between the N-1 nitrogen of the PQ nucleus and the ortho position of the N-2-aryl group. [35S]tert-Butylbicyclophosphorothionate ([35S]TBPS) binding assays and electrophysiological measurements of the effects on GABA-evoked Cl(-) currents at recombinant human alpha(1)beta(2)gamma(2)(L) GABA(A) receptors, expressed in Xenopus laevis oocytes, were used to assess the intrinsic activities of a large series of PQs. With the aim of extracting discriminant information and distinguishing BzR ligands with different profiles of efficacy, 51 PQ derivatives, including full and partial agonists, antagonists, and inverse agonists, were analyzed in a multidimensional chemical descriptor space, defined by the lipophilicity parameter CLOG P and 3-D molecular WHIM descriptors, by means of principal component analysis, k-nearest neighbors (k-NN) method, and linear discriminant analysis (LDA). The classification methods were applied to subsets of pairs of efficacy classes, and lipophilicity and 3-D size descriptors were detected as the discriminant variables by a stepwise linear discriminant analysis. LDA proved to be superior to k-NN, especially in classifying PQ ligands (60-84% of success in prediction ability) into categories of efficacies which were contiguous and quite overlapped in the hyperspace of variables.

Animals↗

PubMed2003

An estrogen-dependent four-gene micronet regulating social recognition: a study with oxytocin and estrogen receptor-alpha and -beta knockout mice.

Estrogens control many physiological and behavioral processes, some of which are connected to reproduction. These include sexual and other social behaviors. Here we implicate four gene products in a micronet required for mammalian social recognition, through which an individual learns to recognize other individuals. Female mice whose genes for the neuropeptide oxytocin (OT) or the estrogen receptor (ER)-beta or ER-alpha had been selectively "knocked out" were deficient specifically in social recognition and social anxiety. There was a remarkable parallelism among results from three separate gene knockouts. The data strongly suggest the involvement in social recognition of the four genes coding for ER-alpha, ER-beta, OT, and the OT receptor. We thus propose here a four-gene micronet, which links hypothalamic and limbic forebrain neurons in the estrogen control over the OT regulation of social recognition. In our model, estrogens act on the OT system at two levels: through ER-beta, they regulate the production of OT in the hypothalamic paraventricular nucleus, and through ER-alpha, they drive the transcription of the OT receptor in the amygdala. The proper operation of a social recognition mechanism allows for the expression of appropriate social behaviors, aggressive or affiliative.

Animals↗