Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Microglia, brain macrophages, are thought to be the primary target of HIV-1 infection in the brain, because they exclusively express the CD4 antigen which is effectively used for viral entry. The expression of CD4 mRNA in cultured microglia could be detected by the reverse-PCR method. Using this and immunohistochemical staining, we found that the immunosuppressants cyclosporin A and FK506 decreased CD4 expression in cultured murine microglia without causing any significant decrease in cell viability. FK506 was more potent than cyclosporin A. Lipopolysaccharide also decreased CD4 mRNA expression in microglia. The effects of immunosuppressants and lipopolysaccharide seemed to be specific for microglia since these chemicals did not alter the CD4 expression in lymphocytes or peritoneal macrophages. These agents, if modified to pass through the blood-brain barrier, may prevent viral spread of HIV-1 infection in the central nervous system and the AIDS-dementia complex.
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PMID:Down regulation of CD4 expression in cultured microglia by immunosuppressants and lipopolysaccharide. 128

Mononuclear cells obtained from human blood were mitogen or antigen activated in vitro in the presence or absence of FK506 or cyclosporin A (CsA). Cytokine production was studied at a single-cell level by ultraviolet (UV) microscopy of fixed permeabilized cells using cytokine-specific monoclonal antibodies (mAb). Phenotypic characterization of the monokine-producing cells was achieved by two-colour immunofluorescent staining. Cytokine production after antigen activation with Staphylococcus aureus enterotoxin A (SEA) was significantly reduced. FK506 or CsA inhibited SEA-induced tumour necrosis factor-alpha (TNF-alpha) production both in monocytes (P less than 0.01) and in lymphocytes (P less than 0.001), at a drug concentration of 1-25 ng/ml for FK506 and 100-500 ng/ml for CsA. Lymphocyte synthesis of interleukin-2 (IL-2), interferon-gamma (IFN-gamma) and TNF-beta after SEA activation was also significantly reduced by either of the drugs. In contrast, endotoxin-induced monokine production (TNF-alpha and IL-6) after lipopolysaccharide (LPS) stimulation was unaffected by FK506 or CsA even when added in concentrations as high as 1000 ng/ml. When the cells were stimulated by phorbol ester (phorbol 12-myristate 13-acetate, PMA) plus calcium ionophore (ionomycin), FK506 and CsA inhibited, in a dose-dependent manner, the production of IL-2, IL-4, IL-5, IFN-gamma and TNF-alpha. The 50% inhibitory concentration (IC50) for FK506 or CsA on the cellular synthesis of the various cytokines varied between 0.6 and 1.0 ng/ml and 20 and 60 ng/ml, respectively. Further stimulation by addition of anti-CD28 mAb to the cultures resulted in an augmented IL-2 and IFN-gamma production which was resistant to both FK506 and CsA. This report delineates extensive similarities between the two drugs in mechanisms of immunosuppression by blockade of identical interleukin production. Depending on the mode of cell activation the two drugs inhibited not only cytokine production in lymphocytes but also antigen-induced monokine (TNF-alpha) production in macrophages, although the optimal immunomodulatory effect of FK506 was achieved at a concentration approximately 50-fold lower than that of CsA.
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PMID:Effects of FK506 and cyclosporin A on cytokine production studied in vitro at a single-cell level. 137 91

The immunosuppressive effects of prodigiosin 25-C were studied in comparison with FK506. Both prodigiosin 25-C and FK506 suppressed T cell proliferation in response to concanavalin A (con A) or phytohemagglutinin (PHA) more significantly than that to lipopolysaccharide. However, prodigiosin 25-C inhibited con A-mediated mitogenic response more strongly than PHA-mediated one. FK506 showed no selectivity among those responses. In addition, when higher concentration of con A was used an inhibitory effect of prodigiosin 25-C became more evident whereas that of FK506 became less evident. Furthermore, prodigiosin 25-C affected neither interleukin-2 (IL-2) production nor IL-2 receptor (IL-2R) and transferrin receptor (TF-R) expression in vitro, though FK506 extensively inhibited IL-2 production and significantly suppressed IL-2R and TF-R expression. When comparing the effects of prodigiosin 25-C and FK506 in vivo by injecting antigens of different nature to a mouse, prodigiosin 25-C selectively inhibited cytotoxic T lymphocyte (CTL) activity induced by an allogenic mastocytoma, P815, without affecting production of antibody against a thymus dependent (TD) antigen, sheep red blood cell (SRBC). On the contrary, FK506 significantly inhibited both CTL induction and the antibody production. When Brucella abortus, a thymus independent (TI) antigen, and SRBC were simultaneously challenged to a mouse, neither prodigiosin 25-C nor FK506 affected antibody production against the TI antigen while the effect on the TD antigen were the same as described above. The present results revealed the unique immunosuppressive property of prodigiosin 25-C which was different from that of FK506.
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PMID:Selective immunosuppression of prodigiosin 25-C and FK506 in the murine immune system. 170 65

A recently discovered immunosuppressive agent, FK506, has been shown to be effective primarily as an inhibitor of T cell responses in vitro, but little is known about its effects on accessory cell function. This study was undertaken to determine the effect of FK506 on interleukin 1 (IL-1) production by macrophages, by using a sensitive and specific enzyme-linked immunosorbent assay. FK506 partially suppressed IL-1 alpha release, from macrophage-like U937 cells stimulated with phorbol myristate acetate and from human monocytes and alveolar macrophages activated with lipopolysaccharide, in a dose-dependent manner. Moreover, it was indicated that FK506 suppressed not only IL-1 release but also IL-1 synthesis itself, by measurement of cell-associated IL-1 alpha of U937 cells. The optimal concentrations of FK506 for suppressing IL-1 alpha did not affect cell viability or proliferation, and were 10- to 100-fold lower than those of cyclosporin A. It is concluded that FK506 affects macrophage physiology, suppressing IL-1 alpha production significantly. Thus, FK506 has the potency to act on non-T cells and the effect on macrophages may play an additional role in preventing graft rejection.
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PMID:Effects of an immunosuppressant, FK506, on interleukin 1 alpha production by human macrophages and a macrophage-like cell line, U937. 170 47

1. The effects of the immunosuppressants cyclosporin A (CsA) and FK506 on nitric oxide (NO) synthesis induced by lipopolysaccharide (LPS) or cytokines were examined in rat vascular smooth muscle cells (VSMC) in culture. 2. CsA inhibited by up to 90% the accumulation of nitrite induced by LPS, but FK506 had a weaker effect on nitrite accumulation induced by LPS in these cells. Both CsA and FK506 (at 1 mumol/L) significantly inhibited nitrite production induced by recombinant murine interleukin-1 beta (rIL-1 beta). 3. Given their differing potency, it is likely that CsA and FK506 suppress induction of NO synthase through different intracellular mechanisms. This action could contribute to the side effects of CsA therapy.
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PMID:Suppression of nitric oxide production by cyclosporin A and FK506A in rat vascular smooth muscle cells. 752 Dec 74

We investigated the effect of the potent immunosuppressive agent, FK506, on experimental glomerular thrombosis in rats by combined injections of nephrotoxic serum (NTS) and lipopolysaccharide (LPS). Either FK506 or placebo was administered intramuscularly three hours prior to injection of NTS that was followed one hour later by LPS. Rats were killed five hours after the LPS injection. Compared with placebo, FK506 pretreatment significantly reduced thrombosis formation, in a dose-dependent manner. FK506 also reduced proteinuria and the rise of serum creatinine level. Early infiltration of polymorphonuclear leukocytes into the glomeruli after LPS injection was significantly suppressed in the FK506 group compared with the placebo group. We also measured serum tumor necrosis factor (TNF) activity by using an L929 fibroblast cytotoxicity assay. Peak serum TNF activity was observed one hour after LPS injection, and FK506 significantly suppressed the elevation. Thrombosis was also developed in athymic nude rats, suggesting thrombosis formation is T cell independent. These data suggest that the FK506 has inhibitory effects on non-lymphocytes and possesses an anti-inflammatory effect in vivo.
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PMID:FK506 inhibits renal glomerular thrombosis induced in rats by nephrotoxic serum and lipopolysaccharide. 752 50

Nitric oxide (NO) is a potent biological messenger molecule in the central nervous system (CNS). There are several potential sources of NO production in the CNS, including neurons and endothelial cells which express NO synthase (NOS) constitutively. Astrocytes and microglia can be induced by cytokines to express a NOS isoform similar to macrophage NOS (mNOS). Primary mixed glial cultures exposed to lipopolysaccharide (LPS) or a combination of LPS and gamma-interferon (INF-gamma) produce nitrite, a breakdown product of NO formation, in a dose-dependent manner. Nitrite production is detectable at 12 hr, peaks at 48 hr and is sustained for at least 96 hr. The NOS inhibitor, nitro-L-arginine (NArg), inhibits nitrite formation, but the immunosuppressant agent, FK506, does not. In mixed glial-neuronal cultures exposed to 50 ng LPS or 5 ng LPS and 1 microgram INF-gamma, neurons begin to die at 48 hr, approx. 24-36 hr after detectable nitrite production. Neurotoxicity is attenuated by 100 microM NArg. These data indicate that expression of inducible mNOS causes delayed neurotoxicity.
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PMID:Expression of inducible nitric oxide synthase causes delayed neurotoxicity in primary mixed neuronal-glial cortical cultures. 753 25

The effect of cyclosporin A on induction of nitric oxide synthase in rat aortic smooth muscle cells was examined. A combination of interleukin-1 alpha (100 U/mL) and tumor necrosis factor--alpha (5000 U/mL) induced accumulation of nitrite/nitrate, the stable end products of nitric oxide, in culture media within 48 hours. Cyclosporin A inhibited this nitrite/nitrate accumulation in a concentration-dependent manner with an IC50 of 4 x 10(-7) mol/L when applied simultaneously with the cytokines. The expression of inducible nitric oxide synthase messenger RNA (mRNA) induced by the combination of interleukin-1 alpha and tumor necrosis factor-alpha was inhibited by the cyclosporin A cotreatment. Cyclosporin A did not decrease inducible nitric oxide synthase mRNA stability in the presence of transcription inhibitor actinomycin D (5 micrograms/mL). Induction of nitrite/nitrate production by the combination of tumor necrosis factor-alpha and bacterial lipopolysaccharide or that of interleukin-1 alpha and interferon gamma (100 U/mL) was also inhibited by cyclosporin A cotreatment. Another inhibitor of calcineurin, FK506 (up to 10(-6) mol/L), had no effect on the induction of nitrite/nitrate production, suggesting the possibility that the inhibitory effect of cyclosporin A may be exerted by means of a novel pathway other than inhibition of calcineurin. These results indicate that cyclosporin A inhibits inducible nitric oxide synthase induction at the mRNA level and that inducible nitric oxide synthase in vascular smooth muscle cells can be a target for cyclosporin A, providing a possible mechanism for the interference of the drug with the balance of vasoactive substances.
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PMID:Cyclosporin A inhibits nitric oxide synthase induction in vascular smooth muscle cells. 753 14

Casein-elicited peritoneal macrophages from mice were cultured either alone or with interferon-gamma (IFN-gamma) and bacterial lipopolysaccharide (LPS), and the effect of cyclosporin A (CsA) and FK506 on NO2- production (due technical difficulties NO2- was taken as the index for NO) was analysed. We observed an inhibitory effect of CsA and FK506 on NO2- production. The IC50 for NO2- production by casein-elicited macrophages was 0.1 microgram/ml for CsA and 0.3 microgram/ml FK506. The effect of both drugs was dose-dependent and was more clear in non-stimulated macrophages. The presence of IFN-gamma and LPS in the culture increased NO2- production by casein-elicited macrophages and partially eliminated the inhibition exerted by CsA and FK506. Both drugs acted directly on the nitric oxide synthase (NOS), since CsA and FK506 reduced by 35% and by 17%, respectively, NOS activity in the crude cytosolic fraction. However, CsA and FK506 did not alter 14CO2 production from [1-14C]glucose, suggesting that the pentose monophosphate pathway activity was not modified. These data add new insight into the interpretation of the immunosuppressive properties of both drugs.
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PMID:Inhibitory effect of cyclosporin A and FK506 on nitric oxide production by cultured macrophages. Evidence of a direct effect on nitric oxide synthase activity. 753 92

We evaluated the effects of the immunosuppressants cyclosporin A (CsA) and FK506 on the synthesis of nitric oxide (NO) induced by bacterial lipopolysaccharide (LPS) in J774 macrophages. CsA and FK506 each inhibited NO production by LPS in a concentration-dependent fashion, but the cytotoxicity was also evident at higher concentrations (100 microM). Neither CsA nor FK506 had any effect on the activity of NO synthase (NOS) that had already been induced. Findings indicated that CsA and FK506 inhibit the induction of NOS, rather than its catalytic activity. CsA and, to a lesser extent, FK506 increased the synthesis of tetrahydrobiopterin (BH4), an essential cofactor of NOS. Thus, inhibition of NO formation by CsA or FK506 is unlikely to associated with a change in BH4 synthesis caused by these agents in LPS-treated J774 macrophages.
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PMID:Effects of cyclosporin A and FK506 on nitric oxide and tetrahydrobiopterin synthesis in bacterial lipopolysaccharide-treated J774 macrophages. 754 50


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