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)

Observations during the last several years on the relationships between bone marrow-derived dendritic cells (DC) and the cells which are in direct contact with them led to the idea that DC may have regulatory properties. Such regulatory properties exerted by DC were noted in experimental cancers in murine systems as well as in human cancers. It was noted that patients with the same type of cancer in which DC are present in the tumor survive longer than patients without DC in the tumor. It is not known how DC can abrogate the development of the metastatic tumor cells in the primary tumor, nor how the tumor cells are capable of abrogating the anticancer activity of the DC and allowing the development of tumor metastases. Studies on the anticancer activity of macrophages revealed that these cells have an inducible Nitric Oxide (NO) synthase (NOS) which utilizes arginine to produce NO. Suppressor macrophages release NO, which inhibits the ribonucleotide reductase and mitochondrial oxidation in tumor cells in vitro. It was also reported (4) that Interferon gamma (IFN-gamma), produced by murine T helper 1 cells, induces NOS activity in macrophages, while T helper 2 cells which produce Interleukin-4 (IL-4) inhibit the expression of NOS in macrophages. The hypothesis presented in this paper suggests that DC have a gene for NOS which is inducible by immunomodulators (e.g. IFN gamma, OK432, LPS) and can be suppressed by cytokines produced by tumor cells (e.g. IL-4, IL-10).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Success and failure of dendritic cell (DC) anticancer activity may be modulated by nitric oxide synthetase (NOS) gene expression: a hypothesis. 768 49

Nitric oxide produced from the amino acid L-arginine is a short-lived free radical produced by many types of cells for a variety of biological functions, including defence against a range of pathogens. NO synthesis via NOS-2 is deeply intertwined in the cytokine network. Thus, expression of NOS-2 is induced by IFN-gamma, TNF and IL-1 as well as microbial products whereas IL-4, IL-10 and TGF-beta down-regulate its synthesis. In spite of this tight regulation, excessive production of NO as a result of immunological stimulation via NOS-2 could have potential toxic effects on hosts. Indeed, large amount of nitric oxide (NO) are produced at sites of inflammation through the action of NOS-2. The role of NO in inflammation is unclear and may depend on the balance between NO and O2-. The somewhat paradoxical effects of NO might indeed be explained by its various chemical forms. Besides, understanding the regulation and function of NOS-2 is likely to lead to therapeutic approaches to treat a number of diseases.
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PMID:[NO, ambivalent effector of non-specific immunity and of inflammation]. 876 35

The importance of nitric oxide (NO) in mediating macrophage functions has been demonstrated, but production of this potent gas has not been examined in Langerhans cells (LC). Using murine LC purified from epidermal cell suspensions and the recently established LC-like cell line derived from newborn BALB/c epidermis (XS-52), it was shown with reverse transcriptase (RT)-PCR that inducible nitric oxide synthase (iNOS) message is present in these cells. Murine keratinocytes did not contain iNOS message. iNOS mRNA was increased in a concentration-dependent manner by lipopolysaccharide (LPS) in purified murine LC and XS-52 cells, and immunofluorescence using an antibody to iNOS revealed bright cytoplasmic staining in LPS-treated XS-52 cells. Anti-iNOS antibody brightly stained LC on human neonatal foreskin cryosections. An increase in NO production by LPS-treated XS-52 cells over 16 h, as measured by the determination of nitrite levels in culture supernatants using the Griess Reaction, was observed. Interferon-gamma (IFNgamma) did not affect NO production on its own. In the presence of LPS and IFNgamma, NO production was 3 times more than observed with LPS alone. NO production was inhibited by the NOS inhibitor L-NAME. Western blots with anti-iNOS antibody demonstrated an increase in iNOS expression in LPS-treated XS-52 cells that was suppressed by IL-10. NO produced in LC may affect LC functions such as microbicidal activity, antigen presentation, and cytotoxicity and may affect adjacent keratinocytes and melanocytes.
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PMID:Langerhans cells express inducible nitric oxide synthase and produce nitric oxide. 894 67

Recent studies suggest that Leishmania major promastigotes infect cultured macrophages in a stealthy fashion, activating little or no host gene expression and often interfering with the host's ability to respond to further stimulation. Here we examined macrophage transcription at early times following infection, when virulent parasites must execute steps required for survival. Stationary-phase promastigotes induced rapid and transient expression of transcripts of the chemokines JE (human MCAF/MCP-1) and KC (human GRO) in bone marrow-derived macrophages from BALB/c mice. JE and KC expression rose four- to sixfold shortly after infection and returned to uninduced levels by 4-24 hr. In contrast, chemokines MIP-1alpha, C10, and RANTES were not induced, nor were TGF-beta, IL-10, IL-12, or i-NOS. Chemokine induction did not occur following ingestion of latex beads, implicating a parasite-specific stimulus. Elevated expression of a subset of chemokines is the earliest known transcriptional response of macrophages to L. major infection and potentially may provide a signal for the initiation of downstream immunological responses which occur in vivo, such as cytokine induction and chemotaxis of monocytes and macrophages. Thus, Leishmania has a remarkable ability to take an active role in either inducing or preventing the expression of distinct sets of host genes during macrophage invasion and successful intracellular parasitism.
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PMID:Leishmania major: promastigotes induce expression of a subset of chemokine genes in murine macrophages. 908 25

Systemic bacterial lipopolysaccharides (LPS) induce inflammatory responses characteristic of sepsis. Instillation of LPS into rat bladder produces a localized inflammatory response similar to that seen in urinary tract infections (UTIs). Four hours after intravesical instillation of LPS, neutrophils infiltrate into the bladder, and mRNA for inducible nitric oxide synthase (iNOS) and the cytokines, interleukin (IL)-6 and IL-10, is detected in rat bladder but not in the kidney. Induction of iNOS protein is inferred because urinary nitrate and cGMP levels are increased 4 hr after LPS intravesical instillation and remain elevated for at least 24 hr. When LPS is injected intraperitoneally, iNOS and IL-6 mRNA are induced both in the bladder and in the kidney. These data are consistent with the effects of intravesical instillation of LPS remaining localized, iNOS activity increases in both particulate and soluble bladder fractions when measured 4 hr after intravesical instillation of LPS. The magnitude of these increases in iNOS activity in the bladder is not as great as when LPS is injected intraperitoneally. Intravesical instillation of LPS induces no increase in lung or kidney NOS activity. The localized inflammatory response produced by intravesical instillation of LPS demonstrates the importance of LPS as a mediator of the host response in UTIs and supports the use of urinary measurements of nitrate and cGMP in humans as indicative of the localized induction of iNOS in UTIs.
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PMID:Bladder instillation and intraperitoneal injection of Escherichia coli lipopolysaccharide up-regulate cytokines and iNOS in rat urinary bladder. 949 84

Pulmonary granulomatous inflammation modulated by IFN-gamma and IL-12 is also associated with augmented inducible nitric oxide synthase (NOS II). To address the role of increased nitric oxide synthesis in this model, mice received daily i.p. injections of NG-nitro-L-arginine-methyl ester (L-NAME; 8 mg/kg) during both the 2-wk immunization period with purified protein-derivative (PPD) and the subsequent lung challenge with PPD-coated Sepharose beads. Other groups of animals received saline, L-NAME or NG-nitro-D-arginine-methyl ester (D-NAME; 8 mg/kg) during the pulmonary embolization period and not the PPD sensitization period. On day 4 post-PPD bead challenge, PCR analysis of the whole lung revealed that NOS II expression appeared to be similar in both of the L-NAME treatment protocols. L-NAME-treated mice in both dosing protocols had lung lesions that were significantly larger than granuloma lesions measured in mice that received saline or D-NAME. The enlarged lesions from L-NAME-treated mice contained markedly greater numbers of neutrophils and eosinophils. Equivalent numbers of PPD-activated dispersed cells from whole lungs of L-NAME-treated mice produced significantly higher levels of IL-4 and IL-10 and smaller amounts of IL-12 and IFN-gamma compared with similar lung cultures derived from control or D-NAME-treated mice. Levels of C-C chemokines such as monocyte chemoattractant protein-1 (MCP-1), C10, and macrophage inflammatory protein-1alpha (MIP-1alpha) were also significantly elevated in lung cultures from L-NAME-treated mice compared with controls. Thus, nitric oxide regulates the size and cellular composition of the Th1-type lung granuloma, possibly through its effects on the cytokine and chemokine profile associated with this lesion.
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PMID:Alteration of the cytokine phenotype in an experimental lung granuloma model by inhibiting nitric oxide. 954

The main factors in the pathogenesis of AIDS-dementia complex (ADC) are analyzed. The author suggests that these factors can be divided into two groups. The "nonspecific" factors present in every immunologic processes manifested by inflammation compose the first group. They are cytotoxic lymphocytes T, the immunoactivation of infected macrophages, cytokines, NO, NOS and iNOS, the increase of the BBB permeability, the accumulation of beta-amyloid precursor protein, excitotoxic amino acids, various and numerous cells adhesion molecules. The second group may contain factors connected with HIV-1 infection of CNS. In the pathogenesis of AIDS an important role is played by toxic glycoproteins gp 120 and gp 41 which are in the coat of HIV-1 virus, nucleotide sequences variability, possibility of various virus replication in various parts of CNS, the participation of lymphokines IL-4 and IL-10, and presence of co-receptors to HIV-1 virus on lymphocytes, macrophages, neurons and microglial cells.
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PMID:HIV-1-infection in the CNS. A pathogenesis of some neurological syndromes in the light of recent investigations. 1007 2

Since nitric oxide (NO) was recognized as a potent microbicidal agent, its role in host defence against intracellular parasites has been widely demonstrated. Recent evidence suggests a role for NO in combating extracellular and multicellular pathogens. This defence activity has been demonstrated toward the larvae of Schistosoma mansoni, microfilariae of Onchocerca linealis, several stages of Brugia malayi and protoscoleces of Echinococcus multilocularis. Many parasites suppress Th1 lymphocytes and directly inhibit NO production by inducing cytokines, such as IL-4, IL-10 and TGF-beta. In this study, we have investigated the effects of Anisakis simplex, an enhancer of Th2-dominant responses, on NO production. We studied the effect of crude extracts (CE) and excretory-secretory (ES) products on the induction of inducible nitric oxide synthase (iNOS) in bacterial lipopolysaccharide (LPS)-treated J774 macrophages. Stimulation of macrophages by LPS (1 microg/ml) increased nitrite concentrations in the culture medium at 24 h. Co-administration of A. simplex products with LPS, dose-dependently reduced the accumulation of nitrite. Nitrite production is due to induction of iNOS, and both L-NAME (N(G)-nitro-L-arginine methyl ester) (50 microM) and dexamethasone (10 microM) inhibited nitrite accumulation (54.2 and 92.1% inhibition, respectively). The inhibition of nitrite production by A. simplex was 42.1-97.8% in the range 4.75-76 microg/well (CE products) and 37.2-61.5% in the range 5-20 microg/well (ES products). Cell viability assayed by the mitochondrial-dependent reduction of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) verified that the inhibition was not due to general cellular toxicity. However, the effects of A. simplex, were reduced when NOS had been induced by prior exposure to LPS and any possible further induction was blocked by cycloheximide, an inhibitor of protein synthesis.
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PMID:Effects of Anisakis simplex on nitric oxide production in J774 macrophages. 1022 90

To investigate the role of nitric oxide (NO), produced by the inducible form of NO synthase (NOS-2) in the development of experimental autoimmune uveoretinitis (EAU), we immunized C57BL/6x129Sv (H-2(b)) mice carrying a targeted disruption of the gene encoding NOS-2 (NOS-2[-/-]), and wild-type (WT) C57BL/6x129Sv controls with interphotoreceptor retinoid binding protein (IRBP). NOS-2[-/-] mice developed a clinical EAU with delayed onset and decreased severity compared to WT controls. The ocular tissues from WT mice contained activated F4/80 macrophages with NOS-2 expression and retinal destruction whereas less intense EAU was detected in NOS-2[-/-] mice. The expression of NOS-2 mRNA was detected in the retina at the peak of EAU in WT. Analysis of cytokine production in the spleen from NOS-2[-/-] mice by RT-PCR showed high levels of IL-10 mRNA. Our results demonstrate that NO is clearly involved in EAU and may be important for the regulation of immune responses through the regulation of IL-10.
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PMID:Delayed onset and decreased severity of experimental autoimmune uveoretinitis in mice lacking nitric oxide synthase type 2. 1102 32

Type 2 cytokines regulate fibrotic liver pathology in mice infected with Schistosoma mansoni. Switching the immune response to a type 1-dominant reaction has proven highly effective at reducing the pathologic response. Activation of NOS-2 is critical, because type 1-deviated/NO synthase 2 (NOS-2)-deficient mice completely fail to control their response. Here, we demonstrate the differential regulation of NOS-2 and arginase type 1 (Arg-1) by type 1/type 2 cytokines in vivo and for the first time show a critical role for arginase in the pathogenesis of schistosomiasis. Using cytokine-deficient mice and two granuloma models, we show that induction of Arg-1 is type 2 cytokine dependent. Schistosome eggs induce Arg-1, while Mycobacterium avium-infected mice develop a dominant NOS-2 response. IFN-gamma suppresses Arg-1 activity, because type 1 polarized IL-4/IL-10-deficient, IL-4/IL-13-deficient, and egg/IL-12-sensitized animals fail to up-regulate Arg-1 following egg exposure. Notably, granuloma size decreases in these type-1-deviated/Arg-1-unresponsive mice, suggesting an important regulatory role for Arg-1 in schistosome egg-induced pathology. To test this hypothesis, we administered difluoromethylornithine to block ornithine-aminodecarboxylase, which uses the product of arginine metabolism, L-ornithine, to generate polyamines. Strikingly, granuloma size and hepatic fibrosis increased in the ornithine-aminodecarboxylase-inhibited mice. Furthermore, we show that type 2 cytokine-stimulated macrophages produce proline under strict arginase control. Together, these data reveal an important regulatory role for the arginase biosynthetic pathway in the regulation of inflammation and demonstrate that differential activation of Arg-1/NOS-2 is a critical determinant in the pathogenesis of granuloma formation.
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PMID:Differential regulation of nitric oxide synthase-2 and arginase-1 by type 1/type 2 cytokines in vivo: granulomatous pathology is shaped by the pattern of L-arginine metabolism. 1171 22


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