Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide synthase (NOS) isoenzymes generate nitric oxide (NO), a sensitive multifunctional intercellular signal molecule. High NO levels are produced by an inducible NOS (iNOS) in activated macrophages in response to proinflammatory agents, many of which also regulate local bone metabolism. NO is a potent inhibitor of osteoclast bone resorption, whereas inhibitors of NOS promote bone resorption both in vitro and in vivo. The possibility that osteoclasts, like macrophages, express a regulated iNOS and produce NO as a potential autocrine signal following inflammatory stimulation was investigated in well-characterized avian marrow-derived osteoclast-like cells. NO production (reflected by medium nitrite levels) was markedly elevated in these cells by the proinflammatory agents lipopolysaccharide (LPS) and the synergistic action of IL-1 alpha, TNF alpha, and IFN gama. inhibitors of NOS activity (aminoguanidine, L-NAME) or iNOS induction (dexamethasone, TGF beta) reduced LPS-stimulated nitrite production. LPS also increased the NOS-associated diaphorase activity of these cells and their reactivity with anti-iNOS antibodies. RT-PCR cloning, using avian osteoclast-like cell RNA and human iNOS primers, yielded a novel 900 bp cDNA with high sequence homology (76%) to human, rat, and mouse iNOS genes. In probing osteoclast-like cell RNA with the PCR-derived iNOS cDNA, a 4.8 kb mRNA species was detected whose levels were greatly increased by LPS. Induction of iNOS mRNA by LPS, or by proinflammatory cytokines, occurred prior to the rise of medium nitrite in time course studies and was diminished by dexamethasone. Moreover, osteoclast-like cells demonstrated an upregulation of NO production and iNOS mRNA by IL-8 and IL-10, regulatory mechanism's not previously described. It is concluded that osteoclast-like cells express a novel iNOS that is upregulated by inflammatory mediators, leading to NO production. Therefore, NO may serve as both a paracrine and autocrine signal for modulating osteoclast bone resorption.
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PMID:Proinflammatory agents, IL-8 and IL-10, upregulate inducible nitric oxide synthase expression and nitric oxide production in avian osteoclast-like cells. 870 87

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

In the present study peripheral T cell tolerance and the occurrence of shock were evaluated in young and old mice after injection of Staphylococcal enterotoxin B (SEB). In young mice SEB immunization leads to tolerance based on deletion and anergy of SEB-reactive V beta 8+ T cells. With aging, mice developed resistance to SEB-induced deletion of V beta 8+ T cells as well as a high sensitivity to toxic shock. Compared to young mice, older mice injected with SEB showed increased serum levels of interferon-gamma (IFN-gamma), interleukin-2 (IL-2) and IL-4. These results were confirmed by reverse transcription-polymerase chain reaction (RT-PCR), as splenic mRNA levels taken 2 h after SEB injection showed higher values of IL-2, IL-4, and IFN-gamma in old mice. In contrast, mRNA levels for FasL and tumour necrosis factor-alpha (TNF-alpha) were lower. No difference in IL-10 mRNA was found. Compared to young mice, old mice showed a high, but statistically not significantly different (P = 0.20), production of nitric oxide (NO). Blocking of IFN-gamma with antibodies or reducing IFN-gamma by depletion of natural killer (NK) cells resulted, respectively, in a complete or partial protection against mortality in aged mice. Suppressing the NO production by the NO synthase inhibitor N-nitro-L-arginine methylester (L-NAME) increased the mortality in both young and old mice, and abrogated clonal deletion in the surviving young mice. In conclusion, in young mice NO production is a key factor in the protection against mortality and the development of clonal deletion after SEB injection. The higher mortality seen in older mice is mainly related to the elevated production of IFN-gamma and occurs despite a sufficient production of NO. The decreased clonal deletion of old mice may be related to their decreased expression of Fas ligand or TNF-alpha after SEB injection.
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PMID:Increased mortality and impaired clonal deletion after staphylococcal enterotoxin B injection in old mice: relation to cytokines and nitric oxide production. 939 29

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

We examined the effects of IL-10 on tumour necrosis factor-alpha (TNF-alpha) and NO production by LPS-activated macrophages and on the ability of these cells to control Trypanosoma cruzi infection. We first observed that the addition of rIL-10 to macrophages of the J774 cell line decreased their synthesis of TNF-alpha but increased their release of NO in a dose-dependent manner. In parallel, treatment of J774 cells with rIL-10 resulted in a better control of T. cruzi infection involving up-regulation of NO synthesis, as it was not observed in presence of N-nitro-L-arginine methyl ester (L-NAME), a competitive inhibitor of NO synthase. The enhancing effect of rIL-10 on NO production was not observed on peritoneal macrophages from wild-type C57Bl/6 mice, but well on macrophages from IL-10 knock-out mice. The control of NO production by endogenous IL-10 was confirmed by the demonstration that neutralization of IL-10 secreted by LPS-activated macrophages from wild-type mice inhibited their production of NO and, in parallel, their ability to control T. cruzi infection. Taken together, these data demonstrate that both exogenous and endogenous IL-10 up-regulate the production of NO by LPS-activated macrophages and improve thereby their ability to clear T. cruzi infection.
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PMID:IL-10 up-regulates nitric oxide (NO) synthesis by lipopolysaccharide (LPS)-activated macrophages: improved control of Trypanosoma cruzi infection. 969 84

Recent studies support the concept that pulmonary granulomatous inflammation directed by interferon (IFN)-gamma, interleukin (IL)-12, and nitric oxide usually resolves in the absence of fibrosis. To determine whether nitric oxide participates in modulating the fibrotic response during the development of pulmonary granulomas in response to purified protein derivative (PPD), mice presensitized to PPD received daily intraperitoneal injections of N(G)-nitro-D-arginine-methyl ester (D-NAME), N(G)-nitro-L-arginine-methyl ester (L-NAME), or aminoguanidine after delivery of PPD-coated beads to the lungs. Eight days later, morphometric analysis of lung granulomas revealed that L-NAME-treated mice when challenged with PPD in vitro for 36 hours had the largest pulmonary granulomas and the greatest collagen deposition among the treated groups. In addition, equivalent numbers of dispersed lung cells from L-NAME- and aminoguanidine-treated mice produced significantly higher levels of IL-4, monocyte chemoattractant protein (MCP)-1, and macrophage inflammatory protein (MIP)-1alpha and significantly lower levels of eotaxin compared with D-NAME-treated mice. Cultures of dispersed lung cells from L-NAME-treated mice also produced significantly more IL-10 and less IL-12 compared with similar numbers of dispersed lung cells from D-NAME-treated mice. Cultures of isolated lung fibroblasts from L-NAME-treated mice expressed higher levels of C-C chemokine receptor 2 (CCR2) and CCR3 mRNA and contained less MCP-1 and eotaxin protein than a similar number of fibroblasts from D-NAME-treated mice. Thus, nitric oxide appears to regulate the deposition of extracellular matrix in lung granulomas through the modulation of the cytokine and chemokine profile of these lesions. Alterations in the cytokine, chemokine, and procollagen profile of this lesion may be a direct effect of nitric oxide on the pulmonary fibroblast and provide an important signal for regulating fibroblast activity during the evolution of chronic lung disease.
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PMID:Collagen deposition in a non-fibrotic lung granuloma model after nitric oxide inhibition. 984 76

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

Nitric oxide (NO) has been implicated, both and paradoxically, as a pro- and anti-inflammatory agent in a wide range of circumstances. It is of common concern that NO can be either up- or downregulated by different inflammatory cytokines. Attempting to assess the contribution of NO to the granulomatous response, we used the in vitro granuloma (IVG) model which consists on a reaction of mononuclear cells around polyacrylamide beads conjugated to antigens. Our assays employed Schistosoma mansoni antigens and human peripheral blood mononuclear cells (PBMC) from schistosomiasis patients. Recently, we have described evidence for a regulatory role of NO, with the aid of an inhibitor of NO synthesis, L-NAME. The addition of L-NAME to IVG cultures elicited an increase on the granuloma formation index. Based on these data we decided to investigate the mechanisms involved in the effects of L-NAME-enhanced granuloma formation. Cytokines and chemokines are involved in inflammatory responses by, particularly the latter, inducing migration and adhesion of leukocytes, which led us on this search for their interactions with NO on granulomatous reaction. We evaluated the cytokine/chemokine-secreting profile of PBMC (treated and not treated with L-NAME) on the IVG reaction in order to investigate how NO could interfere on the release of these soluble mediators. Comparison of cell culture releasing amounts of IL-2, IL-10, TNFalpha, IFNgamma, MIP-1alpha, MCP-1, and RANTES demonstrated that MIP-1alpha had increased levels when NO production was blocked with L-NAME, whereas IL-10 secretion decreased in presence of L-NAME. The other tested cytokines (IL-2, TNFalpha, and IFNgamma) and chemokines (MCP-1 and RANTES) showed no significant differences between the presence or absence of L-NAME. Results obtained in this work suggest that inhibition of NO production could upregulate the IVG reaction on human schistosomiasis through changes in the cytokine/chemokine profile released by PBMC. The mechanisms involved may lead to a MIP-1alpha-increased and IL-10-decreased secretion under our experimental conditions, which could partly account for the previously ascribed IVG-exacerbating action of NO inhibition.
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PMID:Evidence for nitric oxide action on in vitro granuloma formation through pivotal changes in MIP-1alpha and IL-10 release in human schistosomiasis. 1036 86

In this report, we examined the involvement of the cytokines tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-4, and IL-10 as well as nitric oxide (NO) in the lipopolysaccharide (LPS)-induced experimental abortion model in BALB/c mice. Although in vivo administration of LPS in pregnant mice showed a 72% decrease of serum IL-10, no significant difference in serum TNF-alpha, IFN-gamma, and IL-4 levels, compared to controls, could be detected. At the same time, a correlation of fetal abortion and maternal splenomegaly with an important increase of NO synthesis in the serum was obtained. Simultaneous administration of LPS and aminoguanidine (AG; an inhibitor to NO synthase) rescued the LPS-induced fetal abortion, reduced maternal spleen weight to physiological levels, and decreased serum NO concentration to control levels. In vitro experiments showed that LPS directly induced NO production in primary placental cells and the TPOPHO-1 trophoblast cell line by stimulating the inducible isoform of NO synthase, which ultimately could be blocked by the NO synthase inhibitors AG and L-NAME. The results indicate that LPS, despite its beneficial involvement in intracellular infections, participates in inflammatory/autoimmune damage during pregnancy, leading to embryotoxicity, which is closely linked to the NO pathway.
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PMID:Inhibition of nitric oxide production rescues LPS-induced fetal abortion in mice. 1044 53

To elucidate the possible immunoregulatory role of nitric oxide (NO) in cellular xenograft rejection we performed rat-to-mouse skin xenotransplantation. The rat skin engrafted mice were treated with the inducible NO synthase (iNOS) inhibitors, aminoguanidine (AMG, 200 mg/kg) and NG-nitro-L-arginine methyl ester (L-NAME, 60 mg/kg) every other day until rejection. Skin xenograft survival was monitored and immune cell infiltration and intragraft cytokine and chemokine mRNA expressions were analyzed 7 days after grafting. Compared with the control mice, the AMG- and L-NAME treated mice showed delayed xenograft rejection by approximately 3 days (8.9 +/- 0.7 days vs. 11.7 +/- 1.2 and 12.0 +/- 0.9 days, respectively). Infiltrations of CD11b+, MOMA-2+ cells and neutrophils were significantly reduced in both AMG- and L-NAME treated graft but CD4+ and CD8+ cells were not. The expression of cytokines such as IL-1beta, IL-2, IL-6, IL-12 and IFN-gamma in AMG- and L-NAME treated grafts were significantly decreased (P<0.01), whereas IL-10, TNF-alpha and TGF-beta1 were unchanged or enhanced. Additionally, the expressions of CC-chemokines, such as RANTES and MIP-1alpha, were significantly reduced (P<0.01) whereas the expressions of CXC-chemokines, such as IP-10 and MIG, were unchanged. These results imply that prolonged rat-to-mouse skin xenograft survival by iNOS inhibitors may be due to the selective inhibition of pro-inflammatory cytokines and chemokines and suggest the possible regulatory role of NO in cytokine and chemokine expressions during xenotransplant rejection.
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PMID:Inducible nitric oxide synthase inhibitors prolonged the survival of skin xenografts through selective down-regulation of pro-inflammatory cytokine and CC-chemokine expressions. 1455 Oct 33


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