Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Trefoil family factor 2 (TFF2), also known as spasmolytic peptide, is a low-molecular-weight protein that is upregulated in gastric tissues infected with Helicobacter or having other inflammatory conditions, but a precise function is yet to be elucidated. The role of TFF2 in the development of gastritis, colitis, and inflammatory cytokine responses was examined both in vivo and in vitro using wild-type and TFF2 knockout mice. TFF2 knockout and wild-type mice were infected with Helicobacter felis (H. felis) to induce gastritis. Colitis was induced in TFF2 knockout and wild-type mice by administering dextran sodium sulfate (DSS) in drinking water. Histopathology, clinical disease (colitis), and antibody levels (H. felis) were examined. TFF2 expression in tissues was determined by reverse transcriptase PCR, and the inflammatory and proliferative responses of TFF2-expressing macrophages and spleen cells were examined by cytokine enzyme-linked immunosorbent assay, thymidine incorporation, and gene array studies. TFF2 knockout mice have increased susceptibility to H. felis-induced gastritis, with enhanced gastric inflammation. They were also more susceptible to DSS-induced colitis, with prolonged colonic hemorrhage and persistent weight loss. Remarkably, TFF2 expression was not limited to the gastrointestinal tract, as suggested in previous studies, but was also present in macrophages and lymphocytes. The inflammatory and proliferative responses of these immune cell types were dysregulated in TFF2 knockout mice. TFF2-/- cells were hyperresponsive to interleukin 1 beta stimulation but showed normal responses to lipopolysaccharide, suggesting a specific role for TFF2 in interleukin 1 receptor but not Toll-like receptor 4 signaling via their Toll-interleukin 1 resistance domains. TFF2-/- lymphocytes also produced higher levels of interleukin 2 than wild-type cells. Thus, TFF2 was expressed in the gastrointestinal cells and in immune cells and was a negative regulator of gastrointestinal inflammation and immune cell cytokine responses. Our studies suggest that TFF2 not only controls gastrointestinal repair but also regulates mononuclear cell inflammatory responses.
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PMID:Trefoil family factor 2 is expressed in murine gastric and immune cells and controls both gastrointestinal inflammation and systemic immune responses. 1710 60

Toll-like receptors (TLRs) have been known to act as sensors of innate immunity and respond to ligands of microbial and endogenous components. Tissues and cells typical for interface membrane of foreign body reaction were analyzed to evaluate potential role of TLRs in the pathogenesis of the so called "aseptic loosening of total hip replacement." Fourteen cases of interface membrane around aseptic loose total hip replacement implants were stained by single and double immunohistochemical methods to examine cellular localization of toll-like receptor (TLR)-4 and TLR-9. Osteoarthritic synovium was used as control tissues. Cultured macrophages were used to study TLR-4 and TLR-9 mRNA levels by quantitative reverse transcriptase-polymerase chain reaction. The effect of titanium particle stimulation on macrophages was also examined in the culture. Extensive immunolocalization of TLR-4 and TLR-9 positive cells was observed in the synovial membrane-like interface membrane of foreign body granulomas compared with control synovial membranes. TLR and CD68 double staining demonstrated that the TLR positive cells in aseptic loosening were mostly monocyte/macrophages and foreign body giant cells. TLR-4 and TLR-9 mRNA expression was also found in macrophage-colony stimulating factor treated rat macrophages, but this expression decreased (p < 0.05 or less) upon stimulation with titanium particles although matrix metalloproteinase (MMP)-9 mRNA levels used as macrophage activation marker were increased (p = 0.01). The interface membrane around loosening total hip replacement implants is apparently well equipped with TLRs and, thus, probably very sensitive to various structural components of microbes and to endogenous TLR ligands. This seems to be due to recruitment of monocyte/macrophages as particles per se seemed to down-regulate some of the key TLRs. This suppression after particle phagocytosis might prevent excessive and harmful host responses, and injury to innocent bystander cells/tissues.
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PMID:Toll-like receptors in the interface membrane around loosening total hip replacement implants. 1741 64

Hepatitis C virus (HCV) induces inflammatory signals leading to progressive liver damage. The mechanism of HCV involvement in the host's innate immune responses has not been well characterized and little is known about the molecular mechanisms by which immune cells recognize HCV. In this work we studied Toll-like receptor (TLR) 2 and TLR4, in chronic HCV infection, as recently detected important components of the innate immunity in humans, as microbial recognition receptors. The study involved 30 HCV patients; 15 with chronic hepatitis (group I) and 15 with liver cirrhosis (group II), in addition to 10 healthy controls (group III). mRNA expression of TLR2 and TLR4 in peripheral blood mononuclear cells (PBMCs) was examined using reverse transcriptase PCR. This was carried out in relation to quantitative analysis of HCV-RNA by Real time-PCR and serum tumor necrosis factor-alpha (TNF-alpha) estimation by ELISA. Significant correlation was found, in HCV patients, between the viral load and TLR2 (r = 0.704; p < 0.01 in group I & r = 0.629; p <0.05 in group II) and TLR4 (r = 0.549; p < 0.05 in group I & r = 0.596; p < 0.05 in group II) and between TLR2 and TLR4 (r = 0.814; p < 0.001 in group I & r = 699 p < 0.01 in group II). Over expression of TLR2 and TLR4 was detected in chronic hepatitis patients as compared to controls (p < 0.001). In cirrhotic patients down regulation of TLR4 mRNA expression was found when compared to group I chronic hepatitis (p < 0.001), while TLR2 showed steady over expression. A positive correlation was also detected between TLR2 expression and TNF-alpha in HCV patients (r = 0.571; p < 0.05 in group I & r = 0.723; p < 0.01 in group II), while a weak relationship was found between TLR4 and TNF-alpha in cirrhotic patients. (r = 0.359; p > 0.05). TLR2 correlated significantly with the hepatic necroinflammatory activity grade (r = 0.629; p < 0.05 in group I & r 0.502; p < 0.05 in group II), while TLR4 correlated with the fibrosis stage (r = 0.682; p < 0.01). On the other hand no correlation could be detected between TLR2 and TLR4 and the child's grade in cirrhotic patients. It is concluded that TLR2 and TLR4 may play a vital role in HCV recognition, initiation and progression of HCV induced liver diseases. Lager scale studies as well as advanced molecular researches on immune-modulation of TLRs are recommended. This may have the way to a new therapeutic tool for HCV.
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PMID:Significance of toll-like receptors 2 and 4 mRNA expression in chronic hepatitis C virus infection. 1797 58

Understanding the changes in host gene expression that occur with bacterial infection will help to elucidate the basis of molecular genetic control of disease resistance. The effect of infecting chicks with Salmonella enterica serovar Enteritidis on the RNA expression level of Toll-like receptor (TLR) genes, and the correlation between TLR RNA expression level and bacterial burden in the cecum and spleen of young birds was studied. Chicks from two advanced intercross lines were either infected or mock infected with S. enteritidis at 1 day of age. The RNA expression levels of TLR2, TLR4 and TLR5 genes were assessed by quantitative reverse transcriptase-PCR (qRT-PCR) in cecum and spleen tissues harvested at one week post-infection. Infected chicks had significant upregulation of TLR2 RNA expression in spleen, TLR4 RNA expression in both cecum and spleen, and downregulation of TLR5 RNA expression in cecum. Bacterial burden of S. enteritidis in infected birds was not correlated with TLR RNA expression level. Infecting chicks with S. enteritidis caused an increase in TLR2, TLR4 and TLR5 RNA expression level in spleen in males but not in females. The effect of sex on response to S. enteritidis infection suggests a role for TLR signaling pathways in sex-based modulation of immune response to pathogens. High correlation between TLR2 and TLR4 mRNA expression level in cecum of S. enteritidis infected birds suggests coordinated regulation or simultaneous stimulation of these genes by S. enteritidis. In conclusion, this study clearly showed that young chicks respond to S. enteritidis infection by upregulating TLR2, TLR4 RNA expression. The downregulation of TLR5 RNA expression was observed in cecum by S. enteritidis infection, which might be beneficial to protect host cells from overstimulation by bacterial flagellin.
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PMID:Toll-like receptor gene expression in cecum and spleen of advanced intercross line chicks infected with Salmonella enterica serovar Enteritidis. 1839 16

In the present study, we observed the expression of toll-like receptor 4 (TLR4) and its downstream signal pathway in peripheral blood monocytes (PBMs) from patients with acute cerebral infarct (ACI). The expression of TLR4 and MyD88 by PBMs was determined by flow cytometry and reverse transcriptase-polymerase chain reaction, and nuclear factor-kappaB (NF-kappaB) activity was detected by electrophoretic mobility shift assay. Ischemia/reperfusion injury-induced cerebral edema, infarction area, and neurologic impairment scores were determined in MyD88 gene knockout mice. The results indicated a significant increase in circulating TLR4(+) monocytes in ACI patients as compared with the control group and the transient ischemia attack (TIA) group. This change paralleled an elevation in TLR4mRNA transcription and serum tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6 in the ACI and TIA groups. Correlation analysis showed TLR4 expression to significantly correlate with cytokine levels and stroke severity. MyD88mRNA differed insignificantly among the three groups. Compared with wild-type mice, 6 h of cerebral ischemia followed by 24 h of reperfusion did not significantly change cerebral edema, cerebral infarction area, and neurologic impairment scores in MyD88 gene knockout mice. Compared with the control group, serum heat shock protein (HSP) 60 increased significantly in the ACI and TIA groups, leading to NF-kappaB activation in TLR4/CD14-transfected HEK293 cells. It is suggested that upregulated TLR4 expression on PMBs may act as one of the peripheral mechanisms of inflammatory injury after ACI. Moreover, circulating HSP60 may be a ligand for TLR4, which is involved in the peripheral mechanism of inflammatory injury after ACI, possibly through an MyD88-independent signal pathway.
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PMID:Upregulated expression of toll-like receptor 4 in monocytes correlates with severity of acute cerebral infarction. 1852 39

Burkholderia cenocepacia is known to induce a harmful inflammatory response in the airways of cystic fibrosis patients. Toll-like receptors (TLRs) play key roles in sensing microbial-associated molecular patterns and initiating host innate immunity, but their role in the inflammatory response elicited by B. cenocepacia has not been precisely examined. In this study, we evaluated the contribution of TLR2, TLR4 and TLR5 to the signaling pathways triggered by B. cenocepacia in human bronchial epithelial cells. By quantitative reverse transcriptase (RT)-PCR, we demonstrated that the expression of both TLR2 and TLR4 was significantly upregulated by B. cenocepacia infection, whereas TLR5 expression remained unchanged. Using a dominant-negative approach and airway epithelial cells isolated from MyD88(-/-) mice, we found that B. cenocepacia activated a signaling complex that required the adapter molecule MyD88. Moreover, using epithelial cells from TLR2(-/-), TLR4(-/-) or TLR2/4(-/-) mice or cells overexpressing a functional form of TLR5, we established that TLR5, but neither TLR2 nor TLR4, critically regulated B. cenocepacia-induced lung epithelial inflammatory response.
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PMID:TLR 5, but neither TLR2 nor TLR4, is involved in lung epithelial cell response to Burkholderia cenocepacia. 1868 May 20

Vasodilation after coronary artery bypass surgery is a common complication. Inflammatory mediators influence the expression of alpha1-adrenergic receptors. Do patients requiring high doses of postoperative inotropic support have down-regulated alpha-adrenergic receptors? Is there a characteristic pattern of preoperative inflammatory mediator expression that could predict a complicated course after the operation? Forty-four patients undergoing cardiac bypass surgery with extracorporeal circulation were prospectively investigated. Five perioperative blood samples were taken (preoperative, two hours, 12 hours, 36 hours and 72 hours postoperative). The leucocyte mRNA-expression of the three alpha1-adrenergic receptor subtypes (A, B and D) and 11 different pro-inflammatory mediators were investigated with the real-time reverse transcriptase polymerase chain reaction. The patients were divided into three groups (No-noradrenaline [No-NA]= 0 microg/min, Low-noradrenaline [Low-NA]=0.1-7 microg/min, High-noradrenaline [High-NA] >7 microg/min), according to their postoperative noradrenaline requirements. Preoperatively, alpha1(A)-receptor expression was 4.9-fold (High-NA) and 18.7-fold (Low-NA) higher than the No-NA group (P=0.005) and plasma noradrenaline levels were higher in the High-NA group (P=0.005). Across all groups at 12 hours after the operation, alpha1(A) -receptor expression decreased to approximately one-fifth of preoperative levels (P=0.01); but with greater duration and magnitude of relative decrease in the High-NA group. Patients in the No-NA group had significant postoperative increases in leucocyte inflammatory mediator expression for IL-1beta, TLR4, TREM, MPO, MMP9 and TNF genes, whereas the changes in the Low-NA and High-NA groups were not significant. Low preoperative levels of noradrenaline and low expression of alpha1(A)-adrenoreceptors in leucocytes was associated with less probability of requiring noradrenaline support after cardiac surgery.
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PMID:Alpha1-adrenergic receptor mRNA and inflammatory mediator expression in circulating leucocytes after cardiac surgery. 1871 22

In the present study we tested the responsiveness of human corneal epithelial cells (HCECs) and corneal fibroblasts to lipopolysaccharide (LPS), a Toll-like receptor (TLR) 4 ligand. Purified Pseudomonas aeruginosa LPS was used to stimulate telomerase-immortalized HCECs (HUCL) and stromal fibroblast (THK) cell lines. Exposure of cells to LPS induced a time-dependent activation of NF-kappaB in THK but not in HUCL cells, as assessed by an increase in IkappaB-alpha phosphorylation and degradation. Concomitant with NF-kappaB activation, LPS-treated THK cells, but not HUCL cells, produced a significantly larger number of cytokines than control untreated cells. A cell surface biotinylation assay revealed that HUCL cells express TLR4 intracellularly, whereas TLR5 is expressed on the cell surface. Furthermore, reverse transcriptase-PCR analysis revealed that HUCL and primary HCECs, in contrast to THK cells, do not express myeloid differentiation (MD)-2. Thus, our results demonstrate that the LPS unresponsiveness of HCECs might be due to deficient expression of MD-2, an essential component for LPS-TLR4 signaling.
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PMID:Lack of MD-2 expression in human corneal epithelial cells is an underlying mechanism of lipopolysaccharide (LPS) unresponsiveness. 1893 73

Conjunctival epithelial cells serve as a first line of defense against pathogens presented to the innate immune system. The inflammatory response to Gram-negative bacteria is initiated by toll-like receptor 4 (TLR4). This study investigated whether a TLR4 ligand induces production of inflammatory cytokines in human conjunctival epithelial cells (HCECs) through nuclear factor kappa-B (NF-kappaB). HCECs were evaluated for TLR4 expression by reverse transcriptase-polymerase chain reaction, Western blot analysis, and flow cytometric analysis. HCECs were stimulated with various concentrations of lipopolysaccharide (LPS) and the innate immune response was quantified by measuring expression of the inflammatory cytokines IL-6 and IL-8. Functional NF-kappaB activation was examined using a luciferase reporter assay. Expression of TLR4-specific mRNA as well as its corresponding protein was observed in HCECs. Surface and intracellular expression of TLR4 was observed in flow cytometric analysis. Incubation of HCECs with LPS led to secretion of IL-6 and IL-8. Blockade of TLR4- and TNFR-associated factor (TRAF) 6 activity abolished LPS-induced inflammatory response in HCECs and incubation of HCECs with LPS led to activation of the NF-kappaB transcription factor. LPS did not enhance the TLR4 expression at both mRNA and protein levels in HCECs. Our results demonstrate that surface expression of TLR4 in HCECs can elicit a TLR4-mediated innate immune response through TRAF6-NF-kappaB and contribute to an inflammatory environment on the ocular surface.
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PMID:Toll-like receptor 4 initiates an innate immune response to lipopolysaccharide in human conjunctival epithelial cells. 1895 93

Toll-like receptor (TLR) is known to be a mediator of innate immunity, but recent reports have shown that TLR provides a link to adaptive immunity involved in allograft rejection. To explore the expression patterns in various conditions of renal transplantation, we examined TLR subunit mRNA expressions in renal allograft biopsies of acute rejection (AR; n = 11), chronic rejection (CR; n = 15), chronic cyclosporine nephrotoxicity (CsAN; n = 22), and immunoglobulin A nephropathy (IgAN; n = 9) patients. Control tissues (n = 7) were obtained from normal renal cortical tissue of renal cell carcinoma patients. The diagnosis was made according to the Banff 97 classification. The expressions of TLR 2, 3, 4, and 9 mRNA were analyzed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) using SYBR green. Statistical analysis was performed using analysis of variance (ANOVA) and the Student t test. TLR 2 and 3 mRNA expressions were not significantly different in any group (P > .05). In contrast, TLR 4 mRNA expression was significantly increased in all allograft groups compared with that of controls, and significantly higher in the CsAN than other transplant groups (P < .05). TLR 9 mRNA expression was up-regulated in CsAN and IgAN compared with AR and CR (P < .05). These results suggested that TLR4 mRNA expression was increased in renal allograft patients with chronic allograft dysfunction. Further studies are needed to correlate TLR subtypes with various causes of graft dysfunction among renal allograft patients.
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PMID:Toll-like receptor expression in patients with renal allograft dysfunction. 1910 Apr 17


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