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:1.5.1.19 (NOS)
7,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To study the influence of the inflammatory factor---interleukin-10 on nitric oxide (NO) and nitric oxide synthase system of rat aorta, Griess assay, production of (3)H-citrulline and Western blot were used to determine the release of NO, and the activity and expression of nitric oxide synthase, respectively. The results showed that lipopolysaccharide (LPS) stimulated the activity of inducible nitric oxide synthase (iNOS) and the release of NO. 10(-10) 10(-8) g/ml of IL-10 induced the activity and expression of endothelial nitric oxide synthase (eNOS), but not of iNOS. 10(-9) 10(-8) g/ml of IL-10 also downloaded the release of NO, and the activity and expression of iNOS induced by LPS, while 10(-7) g/ml of IL-10 significantly stimulated the activity and expression of iNOS but not eNOS. In summary, IL-10 presents a duple role in NO/NOS system. On the one hand, IL-10 inhibits the activity and expression of iNOS induced by inflammatory factor; on the other hand, IL-10 stimulates the release of endothelial NO.
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PMID:[Influence of interleukin-10 on nitric oxide /nitric oxide synthase system of the aorta]. 1193 Feb 20

We examined the presence of estrogen receptors (ER) in vascular mast cells and a possible genomic effect of estrogens on the expression of mast cell (MC) mediators such as chymase, TNF alpha, NOS and IL-10, which are known to affect the course of atherosclerosis. Immunocytochemical detection of mast cell tryptase and the co-localization of ERs in MCs from abdominal aortic vessels from 10 fertile woman, 10 postmenopausal women and 15 men was performed. The genomic expression of IL-10, TNF alpha, and NOS was analyzed by RT-PCR and chymase activity by spectrophotometry after 24 h incubation with 17-beta estradiol (0.2-0.5 ng/mL) in rat purified peritoneal MCs. A similar number of MCs were found in both intima and adventitia layers from men, and fertile and postmenopausal women, while ERs were detected only in the arterial walls from fertile women. The mRNA expressions of IL-10 and TNF alpha, as well as chymase activity, were not affected. A moderate increment of NO and both NOS, and a reduction in TNF alpha cytotoxicity was observed after incubating peritoneal MCs with 17-beta estradiol at a concentration of 0.5 ng/mL. Taken together, these results indicate that vascular MCs express ERs. The data demonstrate that estrogens can directly modify vascular MC activity. This is a novel mechanism of synergistic cooperation for the protective role of estrogens in the genesis of atherosclerosis.
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PMID:Estrogen receptors in mast cells from arterial walls. 1205 78

In brain astrocytes, nuclear factor kappaB (NF-kappaB) is activated by stimuli that produce cellular stress causing the expression of genes involved in defence, including the inducible nitric oxide synthase (NOS-2). Theiler's murine encephalomyelitis virus (TMEV) induces a persistent CNS infection and chronic immune-mediated demyelination, similar to human multiple sclerosis. The cytokines interleukin (IL)-4 and IL-10 inhibit the expression of proinflammatory cytokines, counteracting the inflammatory process. Our study reports that infection of cultured astrocytes with TMEV resulted in a time-dependent phosphorylation of IkappaBalpha, degradation of IkappaBalpha and IkappaBbeta, activation of NF-kappaB and expression of NOS-2. The proteasome inhibitor MG-132 blocked TMEV-induced nitrite accumulation, NOS-2 mRNA expression and phospho-IkappaBalpha degradation, suggesting NF-kappaB-dependent NOS-2 expression. Pretreatment of astrocytes with IL-4 or IL-10 decreased p65 nuclear translocation, NF-kappaB binding activity and NOS-2 transcription. IL-4 and IL-10 caused an accumulation of IkappaBalpha in TMEV-infected astrocytes without affecting IkappaBbeta levels. The IkappaB kinase activity and the degradation rate of both IkappaBs were not modified by either cytokine, suggesting de novo synthesis of IkappaBalpha. Indeed, IL-4 or IL-10 up-regulated IkappaBalpha mRNA levels after TMEV infection. Therefore, the accumulation of IkappaBalpha might impair the translocation of the NF-kappaB to the nucleus, mediating the inhibition of NF-kappaB activity. Overall, these data suggest a novel mechanism of action of IL-4 and IL-10, which abrogates NOS-2 expression in viral-infected glial cells.
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PMID:Interleukin-4 and interleukin-10 modulate nuclear factor kappaB activity and nitric oxide synthase-2 expression in Theiler's virus-infected brain astrocytes. 1206 72

OBJECTIVE This study focused on the effect of immunoregulatory cytokines on tissue injury after intestinal ischemia/reperfusion (IR). Furthermore, the role of nitric oxide, heme oxygenase-1 (HO-1) and the transcription factor NF-kappaB/Rel in the disease process was evaluated.SUMMARY BACKGROUND DATA Oxidative stress and inflammatory gene products contribute to ischemia/reperfusion injury (IRI). However, expression of stress proteins such as the inducible nitric oxide synthase (NOS-2) and HO-1 might also provide protection against IRI. METHODS IR was achieved in Lewis rats by selective clamping of the superior mesenteric artery. IL-2 or IL-10 was administered intravenously before reperfusion. Animals were killed 1 hour, 4 hours, and 24 hours after reperfusion. Tissue destruction was assessed by hyaluronic acid (HA) and aminoaspartate-transaminase (AST) serum levels, whereas reduction of glutathione (GSH) tissue levels was used as a marker for oxidative stress. Furthermore, the activation of NF-kappaB/Rel and the expression of NOS-2 and HO-1 were analyzed.RESULTS IR resulted in tissue destruction and significantly reduced GSH tissue levels in the intestines and liver. In addition, NF-kappaB/Rel activation and increased NOS-2 and HO-1 mRNA expression were detected in both organs after IR. IL-2 administration resulted in clinical improvement of the animals and was associated with increased NF-kappaB/Rel activation and enhanced NOS-2 and HO-1 mRNA expression. In contrast, IL-10 resulted in increased tissue destruction in both organs and sustained reduction of GSH levels in the intestines. Furthermore, IL-10 administration failed to enhance NF-kappaB/Rel activity, NOS-2 mRNA, or HO-1 mRNA expression after IR. CONCLUSION IL-10 resulted in increased tissue damage after intestinal IR. This detrimental effect of IL-10 might have been the result of reduced NOS-2 and HO-1 mRNA expression. In contrast, the beneficial effect of IL-2 might have relied on increased HO-1 expression and NOS-2 activity. These controversial effects of IL-2 and IL-10 might have been mediated through transcriptional regulation of NOS-2 and HO-1 gene expression.
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PMID:IL-10 increases tissue injury after selective intestinal ischemia/reperfusion. 1283 65

Macrophage/neutrophil-specific IL-4 receptor alpha-deficient mice (LysM(Cre)IL-4Ralpha(-/flox)) were generated to understand the role of IL-4/IL-13 responsive myeloid cells during Type 2 immune responses. LysM(Cre)IL-4Ralpha(-/flox) mice developed protective immunity against Nippostrongylus brasiliensis accompanied by T(H)2 development and goblet cell hyperplasia. In contrast, LysM(Cre)IL-4Ralpha(-/flox) mice were extremely susceptible to Schistosoma mansoni infection with 100% mortality during acute infection. Mortality was not dependent on neutrophils and occurred in the presence of T(H)2/Type 2 responses, granuloma formation, and egg-induced fibrosis. Death was associated with increased T(H)1 cytokines, hepatic and intestinal histopathology, increased NOS-2 activity, impaired egg expulsion, and sepsis. IL-10 was not able to compensate for the absence of IL-4/IL-13-activated alternative macrophages. Together, this shows that alternative macrophages are essential during schistosomiasis for protection against organ injury through downregulation of egg-induced inflammation.
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PMID:Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology. 1514 30

Severe injury induces immune dysfunction resulting in increased susceptibility to opportunistic infections. Previous studies from our laboratory have demonstrated that post-burn immunosuppression is mediated by nitric oxide (NO) due to the increased expression of macrophage inducible nitric oxide synthase (iNOS). In contrast, others suggest that injury causes a phenotypic imbalance in the regulation of Th1- and Th2 immune responses. It is unclear whether or not these apparently divergent mediators of immunosuppression are interrelated. To study this, C57BL/6 mice were subjected to major burn injury and splenocytes were isolated 7 days later and stimulated with antiCD3. Burn injury induced NO-mediated suppression of proliferative responses that was reversed in the presence of the NOS inhibitor L-monomethyl-L-arginine and subsequently mimicked by the addition of the NO donor, S-nitroso-N-acetyl-penicillamine (SNAP). SNAP also dose-dependently suppressed IFN-gamma and IL-2 (Th1), but not IL-4 and IL-10 (Th2) production. Delaying the addition of SNAP to the cultures by 24 h prevented the suppression of IFN-gamma production. The Th2 shift in immune phenotype was independent of cGMP and apoptosis. The addition of SNAP to cell cultures also induced apoptosis, attenuated mitochondrial oxidative metabolism and induced mitochondrial membrane depolarization. However, these detrimental cellular effects of NO were observed only at supra-physiologic concentrations (>250 microM). In conclusion, these findings support the concept that NO induces suppression of cell-mediated immune responses by selective action on Th1 T cells, thereby promoting a Th2 response.
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PMID:Nitric oxide contributes to the development of a post-injury Th2 T-cell phenotype and immune dysfunction. 1664 64

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. Smoking is considered the major cause of the disease. All smokers develop airway inflammation through oxidative stress with macrophages, neutrophiles, lymphocytes, eosinophils, NK-cells and mediators involved. Macrophages through the activation of Nuclear Factor kappa B (NF.-kappaB) release proinflammatory mediators, lymphocyte chemotactic agents and elastolytic enzymes, activate neutrophil driven serine proteases and GM-CSF. Neutrophiles release IL-8 which in turn recruits neutrophils to the airways. In response to cigarette smoke lung epithelium may release TNF-alpha, TGF-beta, IL-1beta, GM-CSF, IL-8 reactive oxygen species (ROS). Increased number of lymphocyte T CD8+ and CD4+ subpopulations may lead to lung epithelium cells apoptosis and necrosis through perphorines and granzyme-B and TNF-alpha activation. Moreover, increased expression of IL-6, IL-10, IL-12, IL-13, and INF-gamma is observed. Authors indicate the possibility of new treatment strategies such as: agents directed against adhesion molecules, chemokines, phosphodiesterase 4, p38 MAPK, NF.-kappaB phosphoinositide-3-kinase gamma, TGF-beta, NOS synthase, serine proteinases and matrix metalloproteinases.
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PMID:[Pathogenesis of chronic obstructive pulmonary disease. Cellular mechanisms (part I)]. 1664 1

Leukocyte activation, inflammatory up-regulation, and microcirculatory disruption associated with ischemia-reperfusion injury are hallmarks in the pathogenesis of acute pancreatitis (AP). NO donors ensure microvascular integrity, while glucocorticoids act as anti-inflammatory and immune modulator drugs. AP was induced by the biliopancreatic duct outlet exclusion-closed duodenal loops (BPDOE-CDLs) model. Treatment with hydrocortisone (6 mg/kg) or prednisolone (0.5 mg/kg) alone or together with DETA-NO (0.5 mg/kg) was done (a)1 hr pre or (b)1 hr post, or (c) 1 hr pre and 4 hr post ,or (d) 4 hr post triggering AP. NOS inhibition by L-NAME (15 mg/kg) and glucocorticoid receptor blockage by mifepristone (3 mg/kg) was considered. AP severity was assessed by biochemical and histopathological analyses. Treatment with glucocorticoids together with DETA-NO 1 hr pre and 4 hr post BPDOE-CDLs reduced serum amylase, lipase, C-reactive protein, IL-6, IL-10, hsp72, and 8-isoprostane as well as pancreatic and lung myeloperoxidase. Acinar and fat necrosis, hemorrhage, and neutrophil infiltrate were also decreased. Hydrocortisone together with DETA-NO rendered the best results. We conclude that AP severity was significantly diminished by glucocorticoids associated with DETA-NO, with the optimal dose and time point of administration being crucial to provide adequate protection against AP.
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PMID:Influence of hydrocortisone, prednisolone, and NO association on the evolution of acute pancreatitis. 1668 59

Endotoxin (LPS), a Gram-negative cell wall component, has potent proinflammatory properties. Acute LPS exposure causes airway inflammation; chronic exposure causes airway hyperreactivity and remodeling. IL-10 is an important antiinflammatory cytokine, which is decreased in patients with airway disease, such as asthma and cystic fibrosis. To examine the physiologic and therapeutic role of IL-10 in acute and chronic LPS-induced airway disease. Mice were exposed to aerosolized LPS once or daily for 4 wk. Endpoints were airway inflammation, airway reactivity to methacholine, extracellular matrix protein expression, and histologic analysis. IL-10-deficient mice developed significantly enhanced airway cellularity and remodeling when compared with C57BL/6 mice after chronic LPS inhalation. However they demonstrated less airway hyperreactivity associated with higher inducible nitric oxide synthase (iNOS), endothelial NOS (eNOS), and lung lavage fluid nitrite levels. In a bone marrow transplantation model, the IL-10 antiinflammatory effect was dependent on the hematopoietic but not on the parenchymal IL-10 expression. Induced epithelial human IL-10 expression protected from the LPS effects and led to decreased collagen production. IL-10 attenuates chronic LPS-induced airway inflammation and remodeling. Physiologically, the antiinflammatory effect of IL-10 is mediated by hematopoietic cells. Therapeutically, adenovirus-driven expression of human IL-10 in airway epithelia is sufficient for its protective effect on inflammation and remodeling. The role of IL-10 on airway hyperreactivity is complex: IL-10 deficiency protects against LPS-induced hyperreactivity, and is associated with higher eNOS, iNOS, and airway nitrate levels.
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PMID:Leukocyte-derived IL-10 reduces subepithelial fibrosis associated with chronically inhaled endotoxin. 1680 36

Headache and/or migraine, a common problem in pediatrics and internal medicine, affect about 5% to 10% children and adolescents, and nearly 30% of middle-aged women. Headache is also one of the most common clinical manifestations of acquired Toxoplasma gondii infection of the central nervous system (CNS) in immunosuppressed subjects. We present 11 apparently nonhuman immunodeficiency virus-infected children aged 7 to 17 years (8 girls, 3 boys) and 1 adult woman with recurrent severe headaches in whom latent chronic CNS T. gondii infection not manifested by enlarged peripheral lymph nodes typical for toxoplasmosis, was found. In 7 patients, the mean serum IgG Toxoplasma antibodies concentration was 189 +/- 85 (SD) IU/mL (range 89 to 300 IU/mL), and in 5 other subjects, the indirect fluorescent antibody test titer ranged from 1:40 to 1:5120 IU/mL (n= <1:10 IU/mL). Some of the patients suffered also from atopic dermatitis (AD) and were exposed to cat and/or other pet allergens, associated with an increased IL-4 and decreased IFN-gamma production. These cytokine irregularities caused limited control of cerebral toxoplasmosis probably because IL-4 down-regulated both the production of IFN-gamma and its activity, and stimulated production of a low NO-producing population of monocytes, which allowed cysts rupture, increased parasite multiplication and finally reactivation of T. gondii infection. The immune studies performed in 4 subjects showed a decreased percentage of T lymphocytes, increased total number of lymphocytes B and serum IgM concentration, and impaired phagocytosis. In addition, few of them had also urinary tract diseases known to produce IL-6 that can mediate immunosuppressive functions, involving induction of the anti-inflammatory cytokine IL-10. These disturbances probably resulted from the host protective immune reactions associated with the chronic latent CNS T. gondii infection/inflammation. This is consistent with significantly lower enzyme indoleamine 2,3-dioxygenase (IDO) activity reported in atopic than in nonatopic individuals, and an important role that IDO and tryptophan degradation pathways plays in both, the host resistance to T. gondii infection and its reactivation. Analysis of literature information on the subjects with different types of headaches caused by foods, medications, and other substances, may suggest that their clinical symptoms and changes in laboratory data result at least in part from interference of these factors with dietary tryptophan biotransformation pathways. Several of these agents caused headache attacks through enhancing NO production via the conversion of arginine to citrulline and NO by the inducible nitric oxide synthase enzyme, which results in the high-output pathway of NO synthesis. This increased production of NO is, however, quickly down-regulated by NO itself because this biomolecule can directly inactivate NOS, may inhibit Ia expression on IFN-gamma-activated macrophages, which would limit antigen-presenting capability, and block T-cell proliferation, thus decreasing the antitoxoplasmatic activity. Moreover, NO inhibits IDO activity, thereby suppressing kynurenine formation, and at least one member of the kynurenine pathway, 3-hydroxyanthranilic acid, has been shown to inhibit NOS enzyme activity, the expression of NOS mRNA, and activation of the inflammatory transcription factor, nuclear factor-kB. In addition, the anti-inflammatory cytokines IL-4 and IL-10, TGF-beta, and a cytokine known as macrophage deactivating factor, have been shown to directly modulate NO production, sometimes expressing synergistic activity. On the other hand, IL-4 and TGF-beta can suppress IDO activity in some cells, for example human monocytes and fibroblasts, which is consistent with metabolic pathways controlled by IDO being a significant contributor to the proinflammatory system. Also, it seems that idiopathic intracranial hypertension, pseudotumor cerebri, and aseptic meningitis, induced by various factors, may result from their interference with IDO and inducible nitric oxide synthase activities, endogenous NO level, and cytokine irregularities which finally affect former T. gondii status 2mo in the brain. All these biochemical disturbances caused by the CNS T. gondii infection/inflammation may also be responsible for the relationship found between neurologic symptoms, such as headache, vertigo, and syncope observed in apparently immunocompetent children and adolescents, and physical and psychiatric symptoms in adulthood. We therefore believe that tests for T. gondii should be performed obligatorily in apparently immunocompetent patients with different types of headaches, even if they have no enlarged peripheral lymph nodes. This may help to avoid overlooking this treatable cause of the CNS disease, markedly reduce costs of hospitalization, diagnosis and treatment, and eventually prevent developing serious neurologic and psychiatric disorders.
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PMID:Recurrent headache as the main symptom of acquired cerebral toxoplasmosis in nonhuman immunodeficiency virus-infected subjects with no lymphadenopathy: the parasite may be responsible for the neurogenic inflammation postulated as a cause of different types of headaches. 1730 77


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