Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P30536 (PBS)
 9,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Invariant natural killer T (iNKT) cells are an important source of both T helper type 1 (Th1) and Th2 cytokines, through which they can exert beneficial, as well as deleterious, effects in a variety of inflammatory diseases. This functional heterogeneity raises the question of how far phenotypically distinct subpopulations are responsible for such contrasting activities. In this study, we identify a particular set of iNKT cells that lack the NK1.1 marker (NK1.1(neg)) and secrete high amounts of interleukin (IL)-17 and low levels of interferon (IFN)-gamma and IL-4. NK1.1(neg) iNKT cells produce IL-17 upon synthetic (alpha-galactosylceramide [alpha-GalCer] or PBS-57), as well as natural (lipopolysaccharides or glycolipids derived from Sphingomonas wittichii and Borrelia burgdorferi), ligand stimulation. NK1.1(neg) iNKT cells are more frequent in the lung, which is consistent with a role in the natural immunity to inhaled antigens. Indeed, airway neutrophilia induced by alpha-GalCer or lipopolysaccharide instillation was significantly reduced in iNKT-cell-deficient Jalpha18(-/-) mice, which produced significantly less IL-17 in their bronchoalveolar lavage fluid than wild-type controls. Furthermore, airway neutrophilia was abolished by a single treatment with neutralizing monoclonal antibody against IL-17 before alpha-GalCer administration. Collectively, our findings reveal that NK1.1(neg) iNKT lymphocytes represent a new population of IL-17-producing cells that can contribute to neutrophil recruitment through preferential IL-17 secretion.
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PMID:Identification of an IL-17-producing NK1.1(neg) iNKT cell population involved in airway neutrophilia. 1747 Jun 41

Translocator protein (18 kDa) (TSPO), previously known as peripheral-type benzodiazepine receptor, is a critical component of the mitochondrial permeability transition pore. Brain inflammation results in the induction of the expression of TSPO in glial cells and some TSPO ligands decrease reactive gliosis after brain injury. However, since some TSPO ligands are neuroprotective, their effects on reactive gliosis may be the consequence of a reduced neurodegeneration. To assess whether TSPO ligands can modulate reactive gliosis in absence of neuronal death, we have tested their effects on the inflammatory response induced in the hippocampus of male rats by the intracerebroventricular infusion of lipopolysaccharide (LPS). LPS treatment did not induce neuronal death, assessed by Fluoro jade-B staining, but increased the number of cells immunoreactive for vimentin and MHC-II, used as markers of reactive astrocytes and reactive microglia, respectively. Furthermore, LPS produced an increase in the number of proliferating microglia. The TSPO ligand PK11195 reduced the number of MHC-II immunoreactive cells and the proliferation of microglia in LPS treated rats. In contrast, another TSPO ligand, Ro5-4864, did not significantly affect the response of microglia to LPS. Neither PK11195 nor Ro5-4864 affected the LPS-mediated increase in the number of vimentin-immunoreactive astrocytes at the time point studied, although PK11195 reduced vimentin immunoreactivity. These findings identify TSPO as a potential target for controlling neural inflammation, showing that the TSPO ligand PK11195 may reduce microglia activation by a mechanism that is independent of the regulation of neuronal survival.
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PMID:Translocator protein 18 kDa is involved in the regulation of reactive gliosis. 1767 68

Neonatal bacterial infection in rats leads to profound hippocampal-dependent memory impairments following a peripheral immune challenge in adulthood. Here, we determined whether neonatal infection plus an immune challenge in adult rats is associated with impaired induction of brain-derived neurotrophic factor (BDNF) within the hippocampus (CA1, CA3, and dentate gyrus) following fear conditioning. BDNF is well characterized for its critical role in learning and memory. Rats injected on postnatal day 4 with PBS (vehicle) or Escherichia coli received as adults either no conditioning or a single 2min trial of fear conditioning. Half of the rats in the conditioned group then received a peripheral injection of 25mug/kg lipopolysaccharide (LPS) and all were sacrificed 1 or 4h later. Basal (unconditioned) BDNF mRNA did not differ between groups. However, following conditioning, neonatal infection with E. coli led to decreased BDNF mRNA induction in all regions compared to PBS-treated rats. This decrease in E. coli-treated rats was accompanied by a large increase in IL-1beta mRNA in CA1. Taken together, these data indicate that early infection strongly influences the induction of IL-1beta and BDNF within distinct regions of the hippocampus, which likely contribute to observed memory impairments in adulthood.
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PMID:Early-life infection leads to altered BDNF and IL-1beta mRNA expression in rat hippocampus following learning in adulthood. 1799 77

Nitric oxide is a potent vasodilator synthesized from l-Arg by NO synthase (NOS). Constitutive NOS in endothelial cells (eNOS) produces transient bursts of NO in low but physiologically effective levels. Activated monocytes and macrophages express inducible NOS (iNOS), which produces copious quantities of NO. Previous studies showed that NO attenuates pulmonary hypertensive responses induced by i.v. injections of lipopolysaccharide (LPS) or cellulose microparticles (MP). The present study determined whether changes in plasma NO concentrations could be used to assess the time course of NO production in response to LPS or MP injections. Broilers were injected i.v. with 1 mL of PBS (control), 1 mL of LPS (1 mg/mL), or 0.4 mL of MP (0.02 g/mL). Plasma samples were collected from 10 different broilers per group at 15, 30, 45, and 60 min and at 2, 3, 4, 5, 6, 8, 10, and 12 h postinjection. Total plasma NO concentrations were analyzed by nitrate + nitrite assay. After PBS or MP injection, plasma NO levels did not change throughout the 12-h period. Nitric oxide measured in the plasma increased in LPS-injected broilers from 4.8 +/- 0.8 microM at 15 min to 46.6 +/- 5.7 microM by 4 h postinjection, reached peak levels of 85.1 +/- 10.6 microM at 5 h, and returned to baseline levels similar to PBS-injected broilers by 12 h postinjection. We conclude that LPS triggered widespread iNOS expression by circulating monocytes and macrophages, resulting in copious NO production as reflected by significant increases in total plasma NO. Proportionally few monocytes and macrophages responded to MP entrapped in pulmonary arterioles. Consequently, NO produced by iNOS in activated leukocytes or by eNOS in the pulmonary vasculature had a minimal impact on total plasma NO. Total plasma NO from broilers did reflect the time course of massive iNOS activation in response to LPS, but biologically relevant quantities of NO produced by iNOS and eNOS activated during the local inflammatory response to entrapped MPs were too low to affect total plasma NO concentrations.
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PMID:Plasma nitric oxide concentrations in broilers after intravenous injections of lipopolysaccharide or microparticles. 1802 1

Oligodendrocytes are vulnerable to CNS injury and disease. Because oligodendrocytes myelinate CNS axons, their death leads to demyelination and impaired axon conductance, which in turn contribute to neurologic deficits. Replacing oligodendrocytes requires proliferation and differentiation of endogenous NG2+ progenitor cells, a process that can be potently influenced by activated macrophages, which are present in most CNS pathologies. To examine the relationship between oligodendrocyte generation and macrophage activation in vivo, we compared the extent of oligodendrocyte loss and NG2 cell proliferation and differentiation after intraspinal microinjection of lipopolysaccharide (a Toll-like receptor-4 agonist) or zymosan (Toll-like receptor-2 agonist) in rats. Controls included injecting vehicle (sterile PBS; negative control) or lysolecithin (positive control for NG2 cell proliferation and oligodendrocyte differentiation). By 14 days postinjection, lipopolysaccharide injection sites displayed a sigficant rise in NG2 cell proliferation and oligodendrocyte differentiation, which exceeded that in vehicle and lysolecithin injections. Additionally, upregulated ciliary neurotrophic factor expression was present in lipopolysaccharide lesions. In contrast, zymosan-activated macrophages produced complete oligodendrocyte loss without stimulating NG2 cell proliferation, oligodendrocyte replacement, or ciliary neurotrophic factor expression. Zymosan also evoked a delayed lesion expansion and primary demyelination of intact myelinated axons around the lesions. These results clearly delineate the dichotomous potential of macrophage activation for influencing NG2 cell proliferation and oligodendrocyte differentiation. Because endogenous Toll-like receptor ligands are often present in injured CNS tissue, these results shed light on possible mechanisms that restrict oligodendrocyte replacement to specific domains of CNS trauma or disease sites.
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PMID:Oligodendrocyte generation is differentially influenced by toll-like receptor (TLR) 2 and TLR4-mediated intraspinal macrophage activation. 1809 Sep 21

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by a selective loss of dopaminergic neurons in the substantia nigra (SN). It has been suggested that microglial inflammation augments the progression of PD. Neuromelanin (NM), a complex polymer pigment found in catecholaminergic neurons, has sparked interest because of the suggestion that NM is involved in cell death in Parkinson's disease, possibly via microglia activation. To further investigate the possible role of NM in the pathogenesis of PD, we conducted in vivo experiments to find out whether microglial cells become activated after injection of human neuromelanin (NM) into (1) the cerebral cortex or (2) the substantia nigra to monitor in this PD-relevant model both microglial activation and possible neurodegeneration. In this study, adult male Wistar rats received an intracerebral injection of either NM, bacterial lipopolysaccharide (LPS, positive control), phosphate-buffered saline (PBS, negative control) or colloidal gold suspension (negative particular control). After different survival times (1, 8 or 12 weeks), brain slices from the cerebral cortex or substantia nigra (SN, 1 week) were stained with Iba-1 and/or GFAP antibody to monitor microglial and astrocytic reaction, and with tyrosine hydroxylase (TH) to monitor dopaminergic cell survival (SN group only). The injection of LPS induced a strong inflammatory response in the cortex as well in the substantia nigra. Similar results could be obtained after NM injection, while the injection of PBS or gold suspension showed only moderate or no glial activation. However, the inflammatory response declined during the time course. In the SN group, there was, apart from strong microglia activation, a significant dopaminergic cell loss after 1 week of survival time. Our findings clearly indicate that extracellular NM could be one of the key molecules leading to microglial activation and neuronal cell death in the substantia nigra. This may be highly relevant to the elucidation of therapeutic strategies in PD.
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PMID:Human neuromelanin induces neuroinflammation and neurodegeneration in the rat substantia nigra: implications for Parkinson's disease. 1834 32

Development and application of therapeutic oligonucleotides rely on proper analysis of binding and uptake. We have used several model oligodeoxynucleotides (ODNs) to analyze binding/uptake by rat and human leukocytes. Here we describe: (1) differences between in vivo and in vitro uptake of ODNs to rat leukocytes, (2) differences after injection of lipopolysaccharide (LPS), (3) large in vitro differences between primary mononuclear cells in PBS, plasma and blood, and (4) differences of ODN uptake between rat and human leukocytes. Our data show that ODN uptake by primary blood cells was different in PBS, plasma and blood. In addition, LPS treatment increased ODN uptake by leukocytes in blood, indicating that pathological conditions may influence ODN uptake. Furthermore, ODN uptake in rat and human blood is also different, suggesting that preclinical ODN uptake data from rat blood cannot easily be extrapolated to the human condition.
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PMID:In vivo and in vitro differences between leukocytic uptake of oligodeoxynucleotides. 1835 Dec 90

To study the activation of macrophage and upregulation of costimulatory molecule of CD40 in lipopolysaccharide- (LPS-) induced acute lung injury (ALI) model, and to investigate the pathogenecy of ALI, mice were randomly divided into two groups. ALI model was created by injecting 0.2 mg/kg LPS in phosphate saline (PBS) in trachea. The pathologic changes of mice lungs were observed by HE staining at 24 and 48 hours after LPS treatment, then the alveolar septum damage, abnormal contraction, alveolar space hyperemia, and neutrophils or other inflammatory cells infiltration in the LPS group, but not in the control group, were observed. The expression of CD40 mRNA and CD40 protein molecules were higher in LPS group as compared to the control group by Northern blot and flow cytometry, respectively. Expression of Toll-like receptor-4 (TLR4) in activated macrophage (AMPhi) was higher in LPS group as compared to the control group by RT-PCR. The activation of NF-kappaB binding to NF-kappaB consensus oligos increased in LPS group by EMSA in macrophage. The concentrations of TNF-alpha, MIP-2, and IL-1beta cytokines from bronchoalveolar lavage fluid (BALF) were increased significantly in LPS group as compared to the control group by ELISA. The activation of AM and upregulation of costimulatory molecule CD40 induced all kinds of inflammatory cytokines releasing, then led to ALI. Therefore, both of them played vital role in the process of development of ALI.
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PMID:The activation of macrophage and upregulation of CD40 costimulatory molecule in lipopolysaccharide-induced acute lung injury. 1846 10

The role of resident cells during the lipopolysaccharide (LPS)-induced neutrophil recruitment into rat air pouches was investigated. In this model, LPS (Escherichia coli, O55: B5 strain; 2-2000 ng) induced a dose- and time-dependent neutrophil recruitment accompanied by the generation of a tumour necrosis factor-alpha (TNFalpha)-like activity. Dexamethasone (0.05-5 mug) and cycloheximide (6 ng), injected 2 h before LPS into the pouches, inhibited the neutrophil recruitment and the generation of the TNFalpha-like activity, while the H1-receptor antagonist mepyramine (1 and 4 mg/kg, i.p., 0.5 h before LPS) and the PAF-receptor antagonist WEB 2170 (0.05 and 1 mg/kg, i.p., 0.5 h before LPS) had no effect. Purified alveolar macrophages (AM) were used to replenish the pouches of cycloheximide-treated recipient rats. AM provided by PBS-treated animals led to the recovery of the LPS-induced neutrophil recruitment and of the TNFalpha-like formation contrasting with those from cycloheximide-treated animals (1 mg/kg, i.p.). When delivered in situ, liposome-encapsulated clodronate, a macrophage depletor, significantly impaired both the LPSinduced neutrophil recruitment and the TNFalpha-like activity. An anti-murine TNFalpha polyclonal antibody (0.5 h before LPS) was also effective. These results emphasize the pivotal role of macrophages for LPS-induced neutrophil recruitment via the formation of TNFalpha.
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PMID:The LPS-induced neutrophil recruitment into rat air pouches is mediated by TNFalpha: likely macrophage origin. 1847 68

The aim of this study was to determine the types of Toll-like receptors (TLRs) expressed in the hen oviduct, and to confirm that vaginal tissue expressing TLR4 responds to lipopolysaccharide (LPS). Healthy laying hens were intravenously or intravaginally injected with LPS, PBS or untreated. The expression pattern of TLRs in the whole oviduct and the effects of LPS on TLR4 and IL-1beta in the vagina were examined by semi-quantitative RT-PCR. The population of cells containing TLR4 protein was examined by immunohistochemistry. The expression of 6 types of TLRs (TLR1 type 2, TLR2, TLR3, TLR4, TLR5 and TLR7) were identified in all segments of the oviduct. The densities of PCR products for each TLR showed a tendency to be greater in the vagina than in the magnum and isthmus. Immunoreactive TLR4 was localized in the epithelial cells and leukocytes in the isthmus, uterus and vagina. Intravenous injection with LPS increased the TLR4 expression and the population of TLR4-immunopositive cells in the vagina. Intravaginal injection with LPS resulted in the increase of leukocytes in the mucosal tissues in association with an increase of TLR4 expression and TLR4-immunopositive cells in the vagina. The IL-1beta expression was also enhanced in a similar manner to that of TLR4. These results suggest that the hen oviduct expresses at least 6 types of TLRs including TLR4 with a greater expression in the vagina. Vaginal tissue expressing TLR4 responds to LPS and in turn upregulate cellular functions to synthesize cytokines. Such expression and functions of TLRs may play an essential role in oviductal innate immunity for host defense.
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PMID:Expression of Toll-like receptors (TLRs) and TLR4 response to lipopolysaccharide in hen oviduct. 1904 76


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