Search PubMed⌕ Search

Biomedical subjects

F Y Liew

Publications and source records attributed to F Y Liew.

At least 91 records · Page 5Linked to original sources
PubMed1995

Glycoinositolphospholipids of Leishmania major inhibit nitric oxide synthesis and reduce leishmanicidal activity in murine macrophages.

Murine macrophages express high levels of inducible nitric oxide (NO) synthase and produce large amounts of nitric oxide when activated with interferon-gamma and lipopolysaccharide in vitro. Nitric oxide is a mediator of a variety of biological functions including microbicidal activity against the protozoan parasite Leishmania species. Glycoinositolphospholipids (GIPL) are the predominant surface glycolipids in both developmental stages of Leishmania major. We report here that GIPL can inhibit the synthesis of NO in a time- and dose-dependent manner. In contrast, lipophosphoglycan, which is present in the promastigote stage did not inhibit NO synthesis. GIPL-treated macrophages also showed markedly reduced leishmanicidal activity. The majority of the inhibitory activity of GIPL was found within the alkylacylglycerol moiety of the GIPL molecule. These data, therefore, suggest that GIPL may contribute towards the survival of the parasite in the immune hosts.

Animals↗
PubMed1995

Administration of nitric oxide synthase inhibitors in experimental autoimmune neuritis and experimental autoimmune encephalomyelitis.

The nitric oxide (NO) synthase pathway is activated during experimental autoimmune inflammation of the central nervous system, and administration of aminoguanidine, an inhibitor of the cytokine-inducible NO synthase (NOS), ameliorated the disease course of autoimmune encephalomyelitis in the SJL mouse. We studied the role of nitric oxide synthase (NOS) in the pathogenesis of experimental autoimmune neuritis (EAN) and experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. NG-L-monomethyl-arginine (L-NMMA), a competitive inhibitor of NOS, partially suppressed T cell line-mediated EAN, but not myelin-induced EAN, myelin basic protein (MBP)-induced EAE, or T cell line-mediated EAE. Aminoguanidine (AG), a selective inhibitor of the cytokine-inducible NOS, enhanced MBP-induced EAE, but had no significant effects on myelin-induced EAN. Two other NOS inhibitors, nitro-arginine methyl-ester and N-nitro arginine, had only little or no effects in EAN and EAE. The administration of NOS inhibitors showed some striking effects in EAN and EAE, but the observed diversity of actions points to a much more complex role of the NO pathway than previously suggested.

Acetates↗
PubMed1995

Nitric oxide and asthmatic inflammation.

Asthmatic patients show an increased expression of inducible nitric oxide synthase (iNOS) in airway epithelial cells and an increased level of nitric oxide (NO) in exhaled air. The NO derived from airway epithelial cells may be a mechanism for amplifying and perpetuating asthmatic inflammation, through inhibition of T helper 1 (Th1) cells and their production of interferon gamma (IFN-gamma). This would result in an increase in the number of Th2 cells and the cytokines interleukin 4 (IL-4) (which is important for IgE expression) and IL-5 (which plays a critical role in the recruitment of eosinophils into the airways). Although this mechanism may be part of our nonspecific airway defence against parasite invasion, it appears to have been activated inappropriately in asthma. Here, Peter Barnes and Eddy Liew argue that the development of specific iNOS inhibitors may represent a novel therapeutic approach for asthma and other allergic diseases.

Amino Acid Oxidoreductases↗
PubMed1995

Regulation of lymphocyte functions by nitric oxide.

Current interest in nitric oxide is derived from its numerous biological roles. Immunologically, apart from the well known role of nitric oxide in anti-microbial and autoimmune diseases, nitric oxide is now emerging as a potential powerful mediator of T-cell responses. Evidence now shows that nitric oxide can both enhance and suppress T-cell functions and that some subsets of T-cell clones can be activated to produce nitric oxide.

Animals↗
PubMed1995

Interactions between cytokines and nitric oxide.

There is now an impressive range of evidence supporting the important role of cytokines in sleep regulation (see Krueger et al., 1995; De Simoni et al., 1995). It has also been reported that inhibition of nitric oxide (NO) synthesis suppresses sleep in rabbits (Kapás et al., 1994). This is not surprising, since NO is closely involved in neurotransmission (Garthwaite, 1991; Schuman and Madison, 1994) and cytokines are the major inducers of NO synthesis (Hibbs et al., 1990). Further, it is now clear that NO plays an important role in modulating immune responses, possibly through the differential regulation of cytokine synthesis (Taylor-Robinson et al., 1994). In this article, I will provide evidence for the interactions between cytokines and nitric oxide, and discuss their implications in the regulation of immune responses. I shall illustrate these mainly with results from my coworkers and I, from our laboratory rather than attempting an exhaustive review of the subject.

Animals↗
PubMed1995

Nitric oxide.

Explore the source record for details and available documents.

Animals↗
PubMed1995

CD4+ but not CD8+ T cells are required for the induction of oral tolerance.

It has been suggested that oral tolerance is mediated by CD8+ T lymphocytes, but the functional properties of these cells are unclear. Here we show that the induction of tolerance by feeding mice ovalbumin (OVA) does not prime antigen-specific class I MHC-restricted cytotoxic T cells in vivo. Indeed, such responses are markedly suppressed in mice fed OVA, and the induction of oral tolerance is abolished by depletion in vivo of CD4+ but not CD8+ T cells. These results indicate that CD8+ lymphocytes are unlikely to play a major role in the induction of oral tolerance and are the first demonstration that specific cytotoxic responses to an exogenous antigen can be suppressed by feeding antigen.

Administration, Oral↗
PubMed1995

Opposing effects of interferon-gamma on iNOS and interleukin-10 expression in lipopolysaccharide- and mycobacterial lipoarabinomannan-stimulated macrophages.

Previous studies have demonstrated that, like bacterial lipopolysaccharide (LPS), arabinofuranosyl-terminated lipoarabinomannan (AraLAM) from an attenuated strain of Mycobacterium induces potent early gene (c-fos, KC, JE and TNF-alpha) responses in murine macrophages, whereas extensively alpha-Manp capped LAM (ManLAM) from virulent M. tuberculosis do not. In this study we have extended analysis of the influence of mycobacterial LAM on macrophage function by demonstrating that AraLAM (but not ManLAM), like bacterial LPS, is a potent stimulator of inducible nitric oxide synthase (iNOS) expression independent of the autocrine activity of co-stimulated tumour necrosis factor-alpha (TNF-alpha) release. The inability of ManLAM to induce iNOS expression was not due to induction of the 'deactivating' cytokine interleukin-10 (IL-10). Indeed, like LPS, AraLAM was also a potent inducer of IL-10 expression. However, analysis of AraLAM- or LPS-induced responses in the presence of interferon-gamma (IFN-gamma) showed that, whereas IFN-gamma acts as a potent co-stimulus for iNOS, it completely inhibits the IL-10 response. Hence, the presence of IFN-gamma early in infection will have an important immunomodulatory role in determining the macrophage response. These results have important implications for the pathogenesis of virulent and avirulent mycobacteria in vivo.

Amino Acid Oxidoreductases↗
PubMed1995

Protection against Leishmania major infection in genetically susceptible BALB/c mice by gp63 delivered orally in attenuated Salmonella typhimurium (AroA- AroD-).

The gene encoding the Leishmania major (L. major) promastigote surface glycoprotein, gp63, was introduced into the Salmonella typhimurium (S. typhimurium) aroA- aroD- live oral vaccine strain BRD509 and expressed under the control of a constitutive tac promoter in plasmid pKK233-2. This construct (GID101) expressed gp63 in vitro and was used to immunize highly susceptible BALB/c mice by the oral route. The plasmid was relatively stably inherited by bacteria growing or persisting in the mesenteric lymph nodes of immunized mice. Mice immunized with GID101 developed significant resistance against a challenge infection with L. major compared to controls immunized with BRD509 alone. Spleen and lymph node cells from immunized mice developed a strong in vitro proliferative T-cell response to killed or live L. major. The activated T cells secreted interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) which was abrogated by treatment with anti-CD4 but not with anti-CD8 antibody. The cells did not produce detectable levels of interleukin-4 (IL-4). The immunized mice also produced significant amounts of leishmanial specific IgG2a antibody but did not develop delayed-type hypersensitivity (DTH) to live parasites. No IgG1 antibody was detected. These data therefore demonstrate that gp63 gene delivered orally by a vaccine strain of S. typhimurium can preferentially induce the development of Th-1 subset of CD4+ T cells and protective immunity in the highly susceptible BALB/c mice.

Animals↗
PubMed1995

Protection against leishmaniasis by injection of DNA encoding a major surface glycoprotein, gp63, of L. major.

cDNA encoding the highly conserved major surface glycoprotein, gp63, of Leishmania major was cloned, together with a signal sequence, into an eukaryotic expression vector, pCDNAI, which carries the human cytomegalovirus (CMV) promoter. This construct, pCMV/glycoprotein 63 (gp63), when injected into the skeletal muscle of BALB/c mice expressed sustained levels of gp63 in the muscle tissue for at least 40 days. Spleen and lymph node cells from the immunized mice produced significant amounts of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) but no detectable IL-4 when cultured with L. major antigens in vitro. The immunized mice also developed significant resistance against L. major infection compared to control mice injected with the empty plasmid. These results suggest that nucleic acid vaccine is effective against parasite infections.

Animals↗
PubMed1995

Expression of TGF-beta in attenuated Salmonella typhimurium: oral administration leads to the reduction of inflammation, IL-2 and IFN-gamma, but enhancement of IL-10, in carrageenin-induced oedema in mice.

Mice injected with carrageenin in the footpad developed local inflammation which peaked at 48 hr. This was significantly reduced in mice inoculated orally with an attenuated Salmonella construct expressing transforming growth factor-beta (TGF-beta). Administration of the Salmonella construct alone had no effect on inflammation. High levels of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) were secreted by draining lymph node cells from mice injected with carrageenin following stimulation in vitro. Prior inoculation with Salmonella enhanced the production of IL-2 and IFN-gamma from the draining lymph node cells. Administration of the Salmonella-TGF-beta construct significantly inhibited the production of these cytokines. In contrast, IL-10 only was secreted from draining lymph node cells of animals inoculated with the Salmonella-TGF-beta construct. Thus, oral administration of TGF-beta can significantly inhibit local inflammation and alter the cytokine secretion pattern of cells from lymph nodes draining the site of inflammation.

Administration, Oral↗
PubMed1995

Nitric oxide in infectious and autoimmune diseases.

Nitric oxide (NO) is a critical mediator of a variety of biological functions. A range of micro-organisms, including viruses, bacteria, protozoa and helminths, is sensitive to NO produced by macrophages activated with gamma-interferon (IFN-gamma) and lipopolysaccharide. In contrast, NO is involved in a number of important immunopathologies, including diabetes, graft-vs-host reaction, rheumatoid arthritis, systemic lupus erythematosus, experimental autoimmune encephalomyelitis and multiple sclerosis. Thus, it is crucial that the synthesis of NO is under tight regulation. This is achieved, in part, through the opposing cytokines produced by T helper 1 (Th1) and Th2 cells. Th1 cells produce IFN-gamma, which is the most powerful inducer of inducible NO synthase (iNOS). In contrast, interleukin 4 is produced by Th2 cells and inhibits the induction of iNOS at the level of transcription. Furthermore, NO is also produced by Th1 cells, whose proliferation can be inhibited by high concentrations of NO. Thus, apart from being a mediator of Th1/Th2 interaction, NO may also be an important self-regulatory molecule that prevents the over-expansion of Th1 cells which are implicated in a range of severe immunopathologies.

Animals↗
PubMed1994

The role of a phosphatidylcholine-specific phospholipase C in the production of diacylglycerol for nitric oxide synthesis in macrophages activated by IFN-gamma and LPS.

Murine macrophages activated by interferon (IFN)-gamma and bacterial lipopolysaccharide (LPS) produce large amounts of nitric oxide (NO), which is a critical mediator for a variety of biological functions. The expression of this inducible NO synthase (iNOS) involves a protein kinase C (PKC)-dependent pathway, but the mechanism for the PKC activation in this system is unclear. Through analysis of diacylglycerol (DAG) synthesis and choline metabolism in activated macrophages, direct evidence is provided that NO synthesis involves the activation of an unusual phosphatidylcholine-specific phospholipase C (PC-PLC) and not a phosphatidylinositol-specific phospholipase C (PI-PLC) or phospholipase D (PLD).

Amino Acid Oxidoreductases↗
PubMed1994

Induction and regulation of CD4+ T cell subsets.

It is now generally accepted that CD4+ T cells can be divided into at least two distinct subsets: Th1 and Th2. Th1 cells characteristically secrete interleukin 1 (IL-2) and gamma-interferon (IFN-gamma) whereas Th2 cells produce mainly IL-4, IL-5 and IL-10. Studies from many laboratories have demonstrated that the balance between these two subsets of T cells frequently determines the outcome of infectious and autoimmune diseases. Several factors influence the preferential induction and regulation of Th1 or Th2 cells in vitro and in vivo. Mice were infected with the protozoan parasite Leishmania to show that the gene encoding a major surface glycoprotein of the parasite, delivered orally in a plasmid carried by an auxotrophic Salmonella typhimurium vaccine strain (BRD509), preferentially induced Th1 cells and protective immunity against a challenge infection. The protective effect of the vaccine was augmented by administration of BRD509 carrying the genes encoding IL-2, IFN-gamma or tumour necrosis factor alpha. Cloned mouse Th1 cells specific for malarial antigens have been used to show that nitric oxide (NO) can inhibit the production of IFN-gamma by Th1 cells. Oral delivery of antigen and selective cytokines may preferentially induce CD4+ T cell subsets. Modulation of NO synthesis may further influence this induction and sustain such selective responses leading to effective therapy.

Administration, Oral↗
PubMed1994

Production of nitric oxide and superoxide by activated macrophages and killing of Leishmania major.

Murine macrophages can be activated to produce nitric oxide (NO) and superoxide and these two radicals can react to form peroxynitrite, a powerful oxidant which may be involved in parasite killing. We now show that murine macrophages activated with zymosan and interferon-gamma (ZYM/IFN-gamma) produced both superoxide (peaking 1-2 h after stimulation, then rapidly declining) and NO (barely detectable at 6 h, peaking by 24 h). Macrophages activated with ZYM alone produced only superoxide, while stimulation with lipopolysaccharide (LPS) and IFN-gamma induced NO but not superoxide. Cells stimulated with ZYM/IFN-gamma or LPS/IFN-gamma killed Leishmania major to a similar degree, an effect that was completely blocked by the addition of N-iminoethyl-L-ornithine. However, macrophages stimulated with ZYM alone were unable to kill L. major. S-nitroso-acetyl-penicillamine, which releases NO, was highly leishmanicidal when added directly to the parasites. 3-morpholino-sydnonimine hydrochloride which releases both NO and superoxide simultaneously, was also efficient at killing L. major and this cytotoxicity was greatly enhanced by the addition of superoxide dismutase. Finally, authentic peroxynitrite failed to induce any cytotoxic effect, even at a high concentration. Thus macrophages can produce either NO, superoxide or both, depending on the stimulus. However, the killing of L. major is dependent only on the production of NO.

Animals↗
PubMed1994

Regulation of the immune response by nitric oxide differentially produced by T helper type 1 and T helper type 2 cells.

The balance between T helper type 1 (Th 1) and T helper type 2 (Th2) cells determines the outcome of many important diseases. Using cloned murine T cell lines, evidence is provided that Th1, but not Th2, cells can be activated by specific antigens or a T cell mitogen, concanavalin A, to produce large amounts of nitric oxide (NO). Furthermore, NO can inhibit the secretion of interleukin (IL)-2 and interferon-gamma by Th1 cells but has no effect on IL-4 production by Th2 cells. Th1 and Th2 cells can, thus, be distinguished by their differential production of and susceptibility to NO. NO exerts a self-regulatory effect on Th1 cells which are implicated in immunopathology.

Animals↗