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)

Although studies have shown that 17beta-estradiol (E(2)) prevents neutrophil infiltration and organ damage following trauma-hemorrhage, the mechanism by which E(2) inhibits neutrophil transmigration remains unknown. Macrophage migration inhibitory factor (MIF) is thought to play a central role in exacerbation of inflammation and is associated with lung injury. MIF regulates the inflammatory response through modulation of Toll-like receptor 4 (TLR4). Activation of TLR4 results in the release of proinflammatory cytokines and chemokines, which induce neutrophil infiltration and subsequent tissue damage. We hypothesized that E(2) mediates its salutary effects in the lung following trauma-hemorrhage via negative regulation of MIF and modulation of TLR4 and cytokine-induced chemotaxis. C3H/HeOuJ mice were subjected to trauma-hemorrhage (mean blood pressure 35 +/- 5 mmHg for approximately 90 min, then resuscitation) or sham operation. Mice received vehicle, E(2), or E(2) in combination with recombinant mouse MIF protein (rMIF). Trauma-hemorrhage increased lung MIF and TLR4 protein levels as well as lung and systemic levels of cytokines/chemokines. Treatment of animals with E(2) following trauma-hemorrhage prevented these changes. However, administration of rMIF protein with E(2) abolished the E(2)-mediated decrease in lung TLR4 levels, lung and plasma levels of IL-6, TNF-alpha, monocyte chemoattractant protein-1, and keratinocyte-derived chemokine (KC). Administration of rMIF protein also prevented E(2)-mediated reduction in neutrophil influx and tissue damage in the lungs following trauma-hemorrhage. These results suggest that the protective effects of E(2) on lung injury following trauma-hemorrhage are mediated via downregulation of lung MIF and TLR4-induced cytokine/chemokine production.
Am J Physiol Lung Cell Mol Physiol 2007 May
PMID:Downregulation of migration inhibitory factor is critical for estrogen-mediated attenuation of lung tissue damage following trauma-hemorrhage. 1727 45

Tumors actively develop different mechanisms such as immunosuppressive cytokine production to escape from immune control and limit the success of immunotherapy. More and more evidences suggest that chronic inflammation contributes to cancer development and progression. Recently, Toll-like receptors (TLRs), the receptors by which immune cells recognize microbial conserved components such as lipopolysaccharide (LPS) then initiate immune and inflammatory responses, have been found to be expressed by some kinds of tumor cells. However, what is the biological function of TLRs on tumor cells and whether human lung cancer cells can express TLRs remain to be fully understood. In the present study, we demonstrate that TLR4 is expressed on human lung cancer cell lines. TLR4 ligation promotes production of immunosuppressive cytokines TGF-beta, VEGF, proangiogenic chemokine IL-8 by human lung cancer cells. In addition, TLR4 ligation induces resistance of human lung cancer cells to TNF-alpha or TRAIL-induced apoptosis. Furthermore, we show p38MAPK activation is necessary for increased VEGF and IL-8 secretion, NF-kappaB activation contributes to apoptosis resistance of human lung cancer cells induced by LPS. Therefore, we demonstrate that TLR4 expressed on human lung cancer cells is functionally active, and may play important roles in promoting immune escape of human lung cancer cells by inducing immunosuppressive cytokines and apoptosis resistance.
Mol Immunol 2007 Apr
PMID:TLR4 signaling promotes immune escape of human lung cancer cells by inducing immunosuppressive cytokines and apoptosis resistance. 3244 54

Activation of eosinophils by microbe-derived molecules via Toll-like receptors (TLR) potentially provides the link between microbe-induced innate immune responses and the exacerbation of allergic inflammation. We investigated the expression of TLRs and the effect of their ligands on human eosinophils. Expression of TLR1-9 was detected by Western blot and flow cytometry. Adhesion molecules, cytokines, superoxides, and eosinophlilic cationic protein (ECP) were assessed by flow cytometry, enzyme-linked immunosorbent assay, chemiluminescent method, and fluorescence immunoassay, respectively. Human eosinophils differentially expressed TLR1, -2, -4, -5, -6, -7, and -9. Peptidoglycan (PGN) (TLR2 ligand), flagellin (TLR5 ligand), and Imiquimod R837 (TLR7 ligand) could significantly upregulate cell surface expression of intercellular adhesion molecule (ICAM)-1 and CD18, and induce the release of IL-1beta, IL-6, IL-8, growth-related oncogene (GRO)-alpha, and superoxides of eosinophils. Only PGN could induce the degranulation for ECP release. However, ds poly I-C (TLR3 ligand), LPS (TLR4 ligand), ssRNA (TLR8 ligand), and CpG-DNA (TLR9 ligand) were much less effective or inactive. PGN, flagellin, and R837 could activate both nuclear factor (NF)-kappaB and extracellular signal-regulated protein kinase (ERK). PGN could activate phosphatidylinositol 3-kinase (PI3K)-Akt, and R837 both PI3K-Akt and p38 mitogen-activated protein kinase (MAPK). The induction of the release of IL-1beta, IL-6, IL-8, GRO-alpha, superoxides, and ECP by PGN, flagellin, and R837 was found to be differentially regulated by NF-kappaB, ERK, PI3K-Akt, and p38 MAPK. The above results therefore support that microbial infection may lead to the exacerbation of allergic inflammation.
Am J Respir Cell Mol Biol 2007 Jul
PMID:Intracellular signaling mechanisms regulating toll-like receptor-mediated activation of eosinophils. 1733 40

Toll-like receptor 4 (TLR4) is key regulators of both innate and adaptive immune responses. TLR4 recognizes pathogen-associated molecular patterns (PAMPs) and activates the inflammatory cells. The function of TLR4 in atherosclerosis has been investigated in mouse knockout studies and epidemiological studies of human TLR4 polymorphisms. These studies have shown that TLR4 function affects the initiation and progression of atherosclerosis. This article reviews the biological functions and clinical implications of TLR4 in atherosclerosis.
J Cell Mol Med
PMID:Toll-like receptor 4 in atherosclerosis. 1736 3

It was recently shown that toll-like receptors (TLR) play a critical role in innate immunity. However, no study has been conducted on TLR expression in hemodialysis (HD) patients. The present study was undertaken to examine innate immunity and the roles played by endotoxins (ET) contained in dialysate in HD patients, by analysis of TLR expression and reactivity. TLR-2 and TLR-4 expression on monocytes was investigated by flow cytometry in the following groups of subjects: healthy controls, patients on HD, patients with end-stage renal disease (ESRD) and patients on peritoneal dialysis (PD). The expression of TLRs on monocytes under stimulation with lipopolysaccharide was also investigated. Expression of TLR-4 was lower in the HD group than in the healthy controls (p<0.05), while expression of TLR-2 was lower in the PD group than in the healthy controls (p<0.05). As the duration of dialysis became longer, TLR-4 expression decreased (p<0.01). TLR-2 was not correlated with duration of dialysis, and the magnitude of decrease in TLR-4 expression following stimulation with ET became smaller (p=0.0006). Suppression of expression of TLR-4 was noted in HD patients, and TLR-4 expression was reduced as the duration of dialysis became longer. Reduced TLR-4 expression may be associated with the compromised immune function in HD patients. It seems possible that chronic stimulation with ET suppresses the expression of TLR-4.
Int J Mol Med 2007 May
PMID:A study of innate immunity in patients with end-stage renal disease: special reference to toll-like receptor-2 and -4 expression in peripheral blood monocytes of hemodialysis patients. 1739 84

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.
Mol Immunol 2007 May
PMID:Various human epithelial cells express functional Toll-like receptors, NOD1 and NOD2 to produce anti-microbial peptides, but not proinflammatory cytokines. 1740 38

Trauma-hemorrhage produces immunodepression in males but not in proestrus females and this difference is due to the presence of high estrogen in proestrus females. Although skin is the largest immunological organ of the body and is considered the first line of defense, no study to-date has examined whether trauma-hemorrhage has any effects on keratinocytes which are the major epidermal cell type (>90%) of skin. We therefore examined whether epidermal keratinocytes inflammatory response and the signal transduction pathways involved in the inflammatory response are altered following trauma-hemorrhage. C3H/HeN mice were subjected to trauma-hemorrhage and 2h thereafter; keratinocytes were harvested and stimulated with LPS for 24h (5 microg/ml). Inflammatory mediators, Toll-like receptor (TLR) and myeloid differentiation adaptor protein (MyD88) expression, and the activation of mitogen-activated protein kinase (MAPK) were determined. Trauma-hemorrhage increased the production of IL-6, IL-10, IL-12 and TNF-alpha enhanced the expression of TLR4, MyD88 as well as the activation of MAPK proteins (p38, ERK and JNK) in epidermal keratinocytes. However, administration of a single dose of 17beta-estradiol following trauma-hemorrhage prevented the increase in these inflammatory parameters under those conditions. These findings suggest that 17beta-estradiol normalizes epidermal keratinocytes inflammatory responses following trauma-hemorrhage by preventing the upregulation of TLR4-mediated MAPK activation.
Mol Immunol 2007 Jul
PMID:17 Beta-estradiol normalizes Toll receptor 4, mitogen activated protein kinases and inflammatory response in epidermal keratinocytes following trauma-hemorrhage. 1740 39

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.
Mol Immunol 2007 Jul
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

Toll-like receptors (TLRs) are cellular receptors that mediate recognition of microbial challenges and the subsequent inflammatory response. Genetic variations within these inflammation-associated genes may alter host-pathogen defence mechanisms affecting susceptibility towards infectious diseases. Taking into account the significance of these genes, we developed a simple and rapid method based in the bi-directional PCR amplification of specific alleles (Bi-PASA) for genotyping known sequence variants in TLR4 (Asp299Gly and Thr399Ile) and TLR9 (T-1237C) genes. This method allows genotype determination in a single reaction and is amenable to large-scale analysis. We used Bi-PASA to characterize the distribution of these polymorphisms in the Portuguese population. A total of 388 randomly selected blood donors of Portuguese origin (203 females and 185 males) were genotyped and allele frequencies were determined. Among the tested individuals, 11.1% and 10.8% were heterozygous for Asp299Gly and Thr399Ile, respectively. In what concerns the T-1237C variation in TLR9, the variant allele was present in 19.4% of the individuals tested. Besides confirming the usefulness of the Bi-PASA in polymorphism analysis, the data presented provide valuable information on TLR polymorphisms in the Portuguese population that can be used to stratify risk patients with increased susceptibility to infection.
Mol Cell Probes 2007 Aug
PMID:Study of disease-relevant polymorphisms in the TLR4 and TLR9 genes: a novel method applied to the analysis of the Portuguese population. 1748 27

Acute endotoxemia is associated with production of acute phase proteins which regulate inflammatory responses to tissue injury. Consistent with DNA microarray experiments, we found that acute endotoxemia, induced by administration of lipopolysaccharide (LPS) to mice (1 mg/kg) or rats (5 mg/kg), resulted in increased expression of the hepatic acute phase protein, lipocalin 24p3, which was evident within 4 h and persisted for 24-48 h. Increases in 24p3 expression were also observed in the lung after LPS administration, as well as in isolated liver and lung macrophages, and Type II alveolar epithelial cells. The actions of LPS are dependent, in part, on Toll-like receptor (TLR) proteins. Macrophages from C3H/HeJ mice, which possess a nonfunctional TLR-4, expressed low levels of 24p3 mRNA when compared to cells from control C3H/OuJ mice. Whereas LPS administration increased 24p3 expression in lung and liver macrophages from control C3H/OuJ mice, minimal effects were observed in TLR-4 mutant mice demonstrating that TLR-4 is important in regulating 24p3 expression during acute endotoxemia. Promoters for genes encoding lipocalin proteins including 24p3 contain consensus sequences for transcription factors including NF-kappaB, and C/EBP. Acute endotoxemia resulted in NF-kappaB nuclear binding activity in both alveolar macrophages and Type II cells. In contrast, C/EBP activation was evident only in Type II cells, suggesting differential effects of LPS on these cell types. These data suggest that the acute phase response to acute endotoxemia involves induction of 24p3 in both the lung and liver. This protein may be important in restoring tissue homeostasis following LPS-induced injury.
Exp Mol Pathol 2007 Oct
PMID:Acute endotoxemia is associated with upregulation of lipocalin 24p3/Lcn2 in lung and liver. 1749 Jun 38


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