Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The interaction between lymphocytes and the resident hepatic macrophage, the Kupffer cell (KC), is relevant to the phenomenon of immune tolerance to Ags entering the liver. Tolerance to Ag administered via the portal vein can be prevented by the rare earth lanthanide metal, gadolinium (Gd). Therefore, we studied the ability of OVA-responsive, H-2d-restricted Th1 clones to proliferate in response to KCs from DBA/2J (H-2d) mice that had been injected with either saline (control) or a Gd solution. Whereas control KCs functioned as effective APCs, KCs from Gd-injected mice (GdKC) were incapable of sustaining the proliferative response of the Th1 clone to the 16 mer of OVA (323-339). This lack of proliferation was determined not to be caused by impaired Ag processing, but rather was the result of IFN-gamma-stimulated nitric oxide (NO) release by the APC: 1) In vitro addition of the nitric oxide synthase (NOS) inhibitor NG-methyl-L-arginine (NMMA) restored the ability of the Gd-treated KC to stimulate clone proliferation. 2) Additional of anti-IFN-gamma, but not anti-IL-2 or anti-IL-4, prevented the induction of NOS in the Gd-exposed KC and was associated with clone proliferation. 3) IFN-gamma levels from clone-GdKC-OVA cocultures closely paralleled the nitrite released by GdKCs. 4) Only the addition of rIFN-gamma, and not IL-2 or IL-4, to cultures of purified GdKCs resulted in the release of nitrite. The results of the study suggest an autocrine loop initiated by the interaction of the clone's TCR with the class II MHC molecule presenting processed OVA on the surface of KC. This interaction stimulates the Th1 lymphocyte to release IFN-gamma, which in turn induces NO release by KCs isolated from Gd-injected mice. This release of NO blocks Th1 proliferation. Such a feedback loop may have particular relevance to Ag-specific tolerance, which is not only induced by the administration of Ag into the portal vein, but is also prevented by Gd pretreatment of the recipient animal.
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PMID:Outcome of Kupffer cell antigen presentation to a cloned murine Th1 lymphocyte depends on the inducibility of nitric oxide synthase by IFN-gamma. 752 42

To assess a potential immunoregulatory role of Schwann cells in the peripheral nervous system we examined whether they are able to secrete nitric oxide metabolites. Schwann cells treated with IFN-gamma and TNF-alpha upregulated iNOS-specific mRNA within 12 hr and released nitrite in a time- and dose-dependent manner, reaching a plateau of secretion after 3 days. Nitrite secretion was inhibited by NMMA, suggesting that Schwann cells are endowed with a cytokine-inducible NO synthase. TGF-beta and IL-1 failed to modulate nitrite release. When assessing their role as APC, we note that Schwann cells activated CD4+ antigen-specific T-cell lines, but in contrast to professional thymic APC this ability declined markedly after Day 1. Theoretically diminished T-cell proliferation and finally death might be achieved by secretion of nitric oxide metabolites by Schwann cells. Inhibition of NO production by NMMA did not restore T-cell proliferation after Day 2 or prevent apoptosis of T-cells. However, in a coculture model Schwann cells exerted a strong suppressive effect on T-cell activation by thymic APC, which was almost completely abrogated by addition of NMMA. We suggest that Schwann cells may exert potent immunoregulatory functions beyond their role as APC. They may terminate immunoinflammatory reactions in the peripheral nervous system by releasing NO.
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PMID:Secretion of nitrite by Schwann cells and its effect on T-cell activation in vitro. 859 41

This study was designed to determine to what extent nitric oxide (NO) mediates the natriuretic and diuretic responses to acute isotonic saline (0.9 gram % NaCl) volume expansion (SVE, 0.5 ml min-1 kg-1). Studies were performed on 49 pentobarbital anesthetized (65 mg/kg) female Sprague-Dawley rats with or without a NO synthase inhibitor, Nomega-nitro-L-arginine (LNA). Group 1 received saline at 27 microliter/min for 1 hr (baseline) and then SVE for 1 hr; Groups 2-4 received LNA at 10, 150, and 200 microgram kg-1 min-1, respectively, for 1 hr followed by LNA + SVE. To determine to what extent inhibition of NOS would reverse an ongoing SVE-induced natriuresis and diuresis, Group 5 was saline-volume-expanded for hours 1 and 2 whereas Group 6 was administered SVE during the first hour and then SVE + 150 microgram kg -1 min-1 LNA during the second hour. SVE caused a significant (P < 0.05) increase in the glomerular filtration rate (GFR) of Group 1 and the LNA-treated rats (Groups 2-4). This SVE-induced increase in the GFR occurred despite the fact that baseline GFR was significantly lower in the two groups of rats that were infused with the highest doses of LNA (Groups 3-4). SVE was also associated with similar increases in urine flow rate, sodium and potassium excretion, and total osmolar excretion in Groups 1-4. On the other hand, mean arterial pressure (MAP) was significantly higher in Group 2 during SVE + LNA and during the baseline as well as during the SVE periods in Groups 3-4; MAP was also significantly elevated in Group 6 during SVE + LNA. Thus, despite the fact that MAP was higher in LNA-treated rats, sodium and urine flow rates were the same as in Group 1 (i.e., there was no evidence of a pressure natriuresis or diuresis in these animals). Along these lines, there was a small but significant positive linear correlation coefficient (r = 0.41, P = 0.05) between sodium excretion values and corresponding MAP values in SVE control rats but not in Groups 3-4 during SVE (r = 0.28, P = 0.26). The current data demonstrate that 1) NO does not mediate SVE-induced hyperfiltration in the rat, 2) NO also does not mediate SVE-induced natriuresis or diuresis, and 3), consistent with other reports, NO appears to mediate pressure natriuresis and diuresis.
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PMID:The role of nitric oxide in saline-induced natriuresis and diuresis in rats. 1046 Jul

Thymocytes maturing in the thymus undergo clonal deletion/apoptosis when they encounter self- or allo-Ags presented by dendritic cells (DCs). How this occurs is a matter of debate, but NO may play a role given its ability of inducing apoptosis of these cells. APC (a mixed population of macrophages (Mphi) and DCs) from rat thymus expressed high levels of inducible NO synthase (iNOS) and produced large amounts of NO in basal conditions whereas iNOS expression and NO production were very low in thymocytes. Analysis by FACS and by double labeling of cytocentrifuged preparations showed that DCs and MPhi both express iNOS within APC. Analysis of a purified preparation of DCs confirmed that these cells express high levels of iNOS and produce large amounts of NO in basal conditions. The capacity of DCs to generate NO was enhanced by exposure to rat albumin, a self-protein, and required a fully expressed process of Ag internalization, processing, and presentation. Peptides derived from portions of class II MHC molecules up-regulate iNOS expression and NO production by DCs as well, both in self and allogeneic combinations, suggesting a role of NO in both self and acquired tolerance. We also found that NO induced apoptosis of rat double-positive thymocytes, the effect being more evident in anti-CD3-stimulated cells. Altogether, the present findings might suggest that DC-derived NO is at least one of the soluble factors regulating events, in the thymus, that follow recognition of self- and allo-Ags.
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PMID:Thymic dendritic cells express inducible nitric oxide synthase and generate nitric oxide in response to self- and alloantigens. 1077 69

Uric acid (UA), a product of purine metabolism, is a known scavenger of peroxynitrite (ONOO(-)), which has been implicated in the pathogenesis of multiple sclerosis and experimental allergic encephalomyelitis (EAE). To determine whether the known therapeutic action of UA in EAE is mediated through its capacity to inactivate ONOO(-) or some other immunoregulatory phenomenon, the effects of UA on Ag presentation, T cell reactivity, Ab production, and evidence of CNS inflammation were assessed. The inclusion of physiological levels of UA in culture effectively inhibited ONOO(-)-mediated oxidation as well as tyrosine nitration, which has been associated with damage in EAE and multiple sclerosis, but had no inhibitory effect on the T cell-proliferative response to myelin basic protein (MBP) or on APC function. In addition, UA treatment was found to have no notable effect on the development of the immune response to MBP in vivo, as measured by the production of MBP-specific Ab and the induction of MBP-specific T cells. The appearance of cells expressing mRNA for inducible NO synthase in the circulation of MBP-immunized mice was also unaffected by UA treatment. However, in UA-treated animals, the blood-CNS barrier breakdown normally associated with EAE did not occur, and inducible NO synthase-positive cells most often failed to reach CNS tissue. These findings are consistent with the notion that UA is therapeutic in EAE by inactivating ONOO(-), or a related molecule, which is produced by activated monocytes and contributes to both enhanced blood-CNS barrier permeability as well as CNS tissue pathology.
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PMID:The peroxynitrite scavenger uric acid prevents inflammatory cell invasion into the central nervous system in experimental allergic encephalomyelitis through maintenance of blood-central nervous system barrier integrity. 1108 92

To assess whether an increased production of nitric oxide is involved in the circulatory and renal alterations of cirrhosis, we evaluated systemic hemodynamics (echocardiography), renal hemodynamics, and sodium handling (lithium clearance method), plasma renin activity (PRA), aldosterone (PAC), and norepinephrine in 7 patients (3 men, mean age 65 +/- 2 years) with compensated cirrhosis, portal hypertension, and hyperdynamic circulation during intravenous N(G)-monomethyl-L-arginine (L-NMMA) (3 mg/kg bolus plus 0.05 mg/kg. min for 120 minutes) or placebo (the vehicle) in a randomized, placebo-controlled, crossover study. Administration of L-NMMA resulted in significant reductions in plasma and urinary nitrite levels and plasma cyclic guanosine monophosphate (cGMP), indicating effective inhibition of nitric oxide synthase. L-NMMA also significantly reduced cardiac index (-13%) and increased systemic vascular resistance (+26%), arterial pressure (+9%), renal blood flow (+12%), glomerular filtration rate (+12%), and sodium excretion (+25%). Changes in sodium excretion were caused by both enhanced filtered sodium load and reduced sodium reabsorption in the proximal tubule. Plasma norepinephrine significantly decreased in response to L-NMMA, and there was a trend for reductions in PRA and PAC. Placebo had no appreciable effect on any of the measured parameters. These results indicate that in patients with compensated cirrhosis, portal hypertension and hyperdynamic circulation inhibition of nitric oxide synthase corrects the altered systemic hemodynamics and improves renal function and sodium excretion.
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PMID:Hemodynamic, renal, and endocrine effects of acute inhibition of nitric oxide synthase in compensated cirrhosis. 1143 29

NO is a cytotoxic and immunomodulatory cytokine produced by macrophages and dendritic cells. We show that stimulation of murine and human macrophages with the heat shock proteins gp96 and hsp70 results in induction of inducible NO synthase and the production of NO. The release of NO by monocytes exposed to hsp60 has been documented previously. Immature, but not mature, dendritic cells respond in the same manner. The activity of heat shock proteins is relatively unaffected by an antagonist of LPS, and is abrogated by heat denaturation. Macrophages have been shown previously to produce NO in response to stimulation with IFN-gamma; stimulation of macrophages with mixtures of IFN-gamma and gp96 or hsp70 leads to a synergistic production of NO. The present observations extend the roles of these heat shock proteins in innate immune responses to another potent and highly conserved function of APC.
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PMID:Heat shock proteins gp96 and hsp70 activate the release of nitric oxide by APCs. 1188 72

Inflammation represents the interaction of the immune and coagulation systems in an attempt to restore normal hemostasis following injury. The underlying basis of the interrelationship between these two physiological systems revolves around the following: a) the activation of coagulation by inflammation, b) the augmentation of the inflammatory response by coagulation, c) the significant attenuation of inflammation by the anticoagulant response and d) the separate influence of the vascular endothelium on coagulation and inflammation as well as its mediation or control of the cross-talk between these two physiological systems. In hemostasis, the protein C anticoagulant pathway is a major mechanism that functions to prevent the development of a pathological thrombus through the regulation of the procoagulant pathway. The endothelium is essential in maintaining a physiological balance between the anticoagulant and procoagulant pathways with proinflammatory cytokines functioning, in part, to regulate endothelial-cell- surface associated coagulation and anticoagulation proteins. In addition to its anticoagulant properties, activated protein C can also function as a regulator of proinflammatory cytokine production. Current evidence suggests that activated protein C may act to control inflammation through NF-kappaB and/or nitric oxide synthase. A better understanding of the relationship between APC and inflammation may provide new targets for drug design.
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PMID:The relationship between inflammation and the anticoagulant pathway: the emerging role of endothelial nitric oxide synthase (eNOS). 1503 95

PD-1 is an immunoinhibitory receptor that belongs to the CD28/CTLA-4 family. B7-H1 (PD-L1) and B7-DC (PD-L2), which belong to the B7 family, have been identified as ligands for PD-1. Paradoxically, it has been reported that both B7-H1 and B7-DC co-stimulate or inhibit T cell proliferation and cytokine production. To determine the role of B7-H1 and B7-DC in T cell-APC interactions, we examined the contribution of B7-H1 and B7-DC to CD4+ T cell activation by B cells, dendritic cells, and macrophages using anti-B7-H1, anti-B7-DC, and anti-PD-1 blocking mAbs. Anti-B7-H1 mAb and its Fab markedly inhibited the proliferation of anti-CD3-stimulated naive CD4+ T cells, but enhanced IL-2 and IFN-gamma production in the presence of macrophages. The inhibition of T cell proliferation by anti-B7-H1 mAb was abolished by neutralizing anti-IFN-gamma mAb. Coculture of CD4+ T cells and macrophages from IFN-gamma-deficient or wild-type mice showed that CD4+ T cell-derived IFN-gamma was mainly responsible for the inhibition of CD4+ T cell proliferation. Anti-B7-H1 mAb induced IFN-gamma-mediated production of NO by macrophages, and inducible NO synthase inhibitors abrogated the inhibition of CD4+ T cell proliferation by anti-B7-H1 mAb. These results indicated that the inhibition of T cell proliferation by anti-B7-H1 mAb was due to enhanced IFN-gamma production, which augmented NO production by macrophages, suggesting a critical role for B7-H1 on macrophages in regulating IFN-gamma production by naive CD4+ T cells and, hence, NO production by macrophages.
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PMID:Blockade of B7-H1 on macrophages suppresses CD4+ T cell proliferation by augmenting IFN-gamma-induced nitric oxide production. 1603 97

The pulmonary hypertensive response to pulmonary vascular obstruction caused by intravenously injected microparticles is amplified by pretreatment with N(omega)nitro-L-arginine methyl ester (L-NAME). The L-NAME prevents the synthesis of the potent vasodilator nitric oxide (NO) by inhibiting both the constitutive [endothelial NO synthase (eNOS or NOS-3)] and inducible [inducible NO synthase (iNOS or NOS-2)] forms of NO synthase. In the present study we used the selective iNOS inhibitor aminoguanidine (AG) to evaluate the role of iNOS in modulating the pulmonary hypertension (PH) triggered by microparticle injections. Experiment 1 was conducted to confirm the ability of AG to inhibit NO synthesis by iNOS in broiler peripheral blood mononuclear cells exposed to bacterial lipopolysaccharide (LPS, endotoxin). Mononuclear leukocytes treated with LPS produced 10-fold more NO than untreated (control) cells. The LPS-stimulated production of NO was partially inhibited by L-NAME and was fully inhibited by AG, thereby confirming that AG inhibits LPS-mediated iNOS activation in broilers. In Experiment 2 we evaluated the responses of male progeny from a base population (MP Base) and from a derivative line selected for one generation from the survivors of an LD50 microparticle injection (MP Select). The pulmonary arterial pressure (PAP) was lower in MP Select than in MP Base broilers. Both lines exhibited similar percentage increases in PAP after microparticles were injected, and AG modestly amplified the PH triggered by microparticles in both lines. In Experiment 3 we evaluated the responses of male progeny from a second base population (PAC Base) and from a derivative line selected for 3 generations using the unilateral pulmonary artery clamp technique (PAC Select). The PAP was lower in PAC Select than in PAC Base broilers, and both lines exhibited similar percentage increases in PAP in response to the microparticles. The PH triggered by microparticles was not amplified by AG but was doubled by L-NAME. These experiments demonstrate that during the 30 min following pulmonary vascular entrapment of microparticles, iNOS modulated the PH elicited in broilers derived from the MP pedigree line, but not in broilers from the PAC pedigree line. Different NOS-mediated responses among broiler populations may affect pulmonary hemodynamic characteristics of broiler lines selected using i.v. microparticle injections.
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PMID:Influence of aminoguanidine, an inhibitor of inducible nitric oxide synthase, on the pulmonary hypertensive response to microparticle injections in broilers. 1655 84


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