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J Magae

Publications and source records attributed to J Magae.

At least 55 records · Page 3Linked to original sources
PubMed1992

Immunomodulating properties of prodigiosin 25-C, an antibiotic which preferentially suppresses induction of cytotoxic T cells.

An antibiotic, prodigiosin 25-C, preferentially suppresses cytotoxic T lymphocytes (CTL) without affecting antibody production. Here, we investigated the effect of prodigiosin 25-C on delayed-type hypersensitivity (DTH), graft versus host reaction (GvHR) and allogeneic skin graft rejection. DTH reactions were markedly inhibited by ip treatment of the mice with prodigiosin 25-C. Cell transfer experiments indicated that prodigiosin 25-C exerted its suppressive effect on the late efferent phase rather than on the induction phase of DTH. Prodigiosin 25-C suppressed induction of anti-host CTL when GvHR was induced by iv inoculating splenocytes of parental C57BL/6 mice to adult unirradiated BDF1 mice. It had little effect on GvHR-induced splenomegaly observed 2 weeks after the inoculation, but significantly delayed the subsidence of splenomegaly as revealed 8 weeks later, suggesting that suppression of CTL converts immunosuppressive GvHR to immunostimulative one as reported by G. M. Shearer. However, reduction of interleukin-2 (IL-2) production and mitogen responses induced by GvHR were not rescued by prodigiosin 25-C treatment. Prodigiosin 25-C moderately prolonged survival of major histocompatibility (MHC)-mismatched skin grafts. Since the mode of action of prodigiosin 25-C is distinct from those of cyclosporin A and FK506, these results demonstrate potential usefulness of the antibiotic for a supplementary immunosuppressant.

Animals↗
PubMed1992

Enhancement by concanavalin A of the suppressive effect of prodigiosin 25-C on proliferation of murine splenocytes.

Proliferation of concanavalin A (Con A)-activated nylon-wool purified murine splenic T cells was increasingly suppressed by prodigiosin 25-C as higher concentrations of Con A were used for the activation. Enhancement of suppressive effect of prodigiosin 25-C was not observed when T cells were stimulated with phytohemagglutinin (PHA), anti-CD3 antibody, or allogeneic splenic adherent cells. The suppressive effect of prodigiosin 25-C was enhanced by the addition of Con A in various T cell subpopulations as well as in LPS-activated splenic B cells. Lectins that recognize mannose residue of biantennary-complex-type sugar chains significantly enhanced the suppressive effect of prodigiosin 25-C, whereas a lectin that binds to N-acetylglucosamine did not. These results suggest that binding of lectins to the mannose residue of biantennary-complex-type sugar chains on cell surface of both T and B lymphocytes plays a central role on the enhancement of the suppressive effect of prodigiosin 25-C.

Animals↗
PubMed1992

Effects of prodigiosin 25-C on cultured cell lines: its similarity to monovalent polyether ionophores and vacuolar type H(+)-ATPase inhibitors.

Prodigiosin 25-C inhibited the proliferation of various cultured cell lines more strongly when concanavalin A (Con A) was added to the cultures. The increase in sensitivity was most evident in T lymphoma YAC-1 cells. The combination of prodigiosin 25-C and Con A induced characteristic morphological changes in these cells. In the presence of Con A, monovalent polyether ionophores and vacuolar type H(+)-ATPase inhibitors induced effects similar to those of prodigiosin 25-C on YAC-1 cells. Prodigiosin 25-C had neither K+ionophore activity nor inhibitory effect on vacuolar type H(+)-ATPase. A Golgi mannosidase II inhibitor, swainsonine, inhibited the proliferation of YAC-1 cells only when Con A was added. Prodigiosin 25-C and swainsonine increased Con A binding receptors on the surface of YAC-1 cells. These results suggest that prodigiosin 25-C affects the intracellular transport and/or processing of glycoproteins.

Biological Transport↗
PubMed1992

Respiratory burst induced by phorbol ester in the presence of tautomycin, a novel inhibitor of protein phosphatases.

Phorbol dibutyrate induced a nitroblue tetrazolium-reducing reaction in differentiated HL-60 cells, which was inhibited by protein kinase inhibitors such as staurosporine and H-7. ID50 of staurosporine and H-7 were 1.4 ng/ml and 0.19 mM, respectively. When tautomycin, an inhibitor of protein phosphatases, was added with the kinase inhibitors, the nitroblue tetrazolium-reducing reaction again appeared. ID50 of staurosporine was 510 ng/ml in the presence of tautomycin. Tautomycin itself weakly induced the reaction, which was inhibited by kinase inhibitors. Such a competitive effect between tautomycin and staurosporine was not observed in a cell-free system of protein kinase C. Okadaic acid had the same effect as tautomycin. The similar results were obtained when respiratory burst was quantitated by measuring H2O2 produced by canine peripheral neutrophils. The mechanism of competitive effect of tautomycin and staurosporine on respiratory burst is discussed.

Alkaloids↗
PubMed1992

Effects of tautomycin, a protein phosphatase inhibitor, on recycling of mammalian cell surface molecules.

The effects of tautomycin, a protein phosphatase inhibitor, on recycling of cell surface molecules were studied with transferrin receptor (TFR) of human myeloid leukemia K562 cells and with CD4 of murine thymocytes. Tautomycin increased expression of TFR of K562 cells whereas phorbol dibutylate (PDBu) decreased it. Tautomycin inhibited PDBu-induced down-regulation of CD4 although it did not induce up-regulation. Okadaic acid also inhibited down-regulation of CD4 which was induced by PDBu. The results suggest that certain inhibitors of protein phosphatases preferentially inhibit endocytosis of cell surface molecules.

Alkaloids↗
PubMed1991

A novel protein phosphatase inhibitor, tautomycin. Effect on smooth muscle.

The antibiotic, tautomycin, was found to be a potent inhibitor of protein phosphatases and equally effective for the type-1 and type-2A enzymes. For the catalytic subunits of the type-1 and type-2A phosphatases the IC50 value was 22 to 32 nM. For the phosphatase activity present in chicken gizzard actomyosin the IC50 value was 6 nM. Tautomycin had no effect on myosin light chain kinase activity. Tautomycin induced a Ca(2+)-independent contraction of intact and permeabilized smooth muscle fibers and this was accompanied by an increase in the level of myosin phosphorylation. Thus, tautomycin by virtue of its ability to inhibit phosphatase activity is a valuable addition for studying the role of protein phosphorylation.

Animals↗
PubMed1990

Selective immunosuppression of prodigiosin 25-C and FK506 in the murine immune system.

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.

Animals↗
PubMed1989

Suppression of cytotoxic T cell induction in vivo by prodigiosin 25-C.

Prodigiosin 25-C (PrG25-C) was discovered as an immunosuppressant in the course of our screening for immunomodulating substances. In this system, PrG25-C inhibited T lymphocytes proliferation and was less suppressive against B lymphocytes. PrG25-C was also a powerful inhibitor of cytotoxic T cell induction by mixed lymphocyte reaction and completely suppressed induction of H-2 specific cytotoxic cells at 12.7 nM. PrG25-C also inhibited in vivo induction of H-2 restricted cytotoxic T lymphocytes at a dose of 0.5 mg/kg but had little myelotoxicity because numbers of blood leukocytes and splenocytes of PrG25-C-treated mice were comparable to those of nonsensitized mice. No inhibitory effects of PrG25-C were observed on the production of anti-SRBC antibody. These results indicate that PrG25-C is a T-lymphocyte-specific immunosuppressant.

Animals↗
PubMed1989

Comparison of the effect of tautomycin and phorbol ester on protein kinase C in a cell-free system.

The effect of tautomycin (TM) on protein kinase C (PKC) was studied in a cell-free system. TM, like phorbol dibutyrate (PDBu), enhanced both base-line and Ca2+/phospholipids-dependent protein kinase activity. However, PDBu but not TM increased the affinity of the enzyme for calcium ions (Ca2+), suggesting that TM is a new activator of PKC, distinct from PDBu. In the presence of 10 micrograms/ml phosphatidyl inositol, the activity of PKC reached maximum at 10(-3) M Ca2+ concentration when the other co-factors were absent. Both TM and PDBu increased the maximum level of PKC activity at the optimum concentration of Ca2+, suggesting that they interacted with the site of PKC which is distinct from the site where Ca2+ interacts. TM and PDBu did not activate the enzyme when protamine sulfate in place of histone III-S was used as a substrate, indicating that they activate PKC by affecting the regulatory domain of the enzyme.

Antifungal Agents↗
PubMed1988

Rapid screening method for inhibitors of protein kinase C.

Specific inhibitors of protein kinase C (PKC) were screened for with a unique detection system, named bleb forming assay. When K562, a human chronic myeloid leukemia cell, was treated with phorbol 12,13-dibutylate (PDBu) or teleocidin which are activators of PKC, many blebs appeared on the cell surface of K562 within 10 minutes. This appearance of blebs is inhibited by staurosporine and H7 which are known to be PKC inhibitors. Teleocidin and PDBu did not induce bleb formation of HL60, a human acute promyelocytic leukemia cell, and the mouse Friend leukemia cell, even though their morphology was changed 24 hours after treatment with teleocidin or PDBu. Many inducers of terminal differentiation of K562 have the same effect on HL60 and Friend cells. However, the bleb inducing activity of PKC activators seems to be specific for K562. The bleb forming assay satisfied the criteria (simplicity and specificity) required for preliminary screening of activators or inhibitors of PKC. Teleocidins A and B, and tautomycin (a new antibiotic isolated in our laboratory) were identified as activators of PKC, and also staurosporine and isoflavones (daidzein and genistein) as inhibitors.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1988

Induction of morphological change of human myeloid leukemia and activation of protein kinase C by a novel antibiotic, tautomycin.

A novel antibiotic tautomycin induced many blebs on the surface of K562 human chronic myeloid leukemia cells, similar to the morphological changes induced by phorbol esters. However, tautomycin did not induce nitroblue tetrazolium reducing activity, when HL60 human promyelocytic leukemia cells were caused to differentiate by quinomycin into mature granulocytes. It did not induce spread of HL60 cells, one of the phenotypes of mature macrophages. In addition, it did not compete with phorbol dibutyrate to bind to the cell surface of K562 cells. However, tautomycin significantly activated protein kinase C (PKC) extracted from K562 cells. These results indicate that tautomycin is a new activator of PKC, distinct from phorbol esters.

Anti-Bacterial Agents↗
PubMed1988

Antitumor and antimetastatic activity of an antibiotic, ascofuranone, and activation of phagocytes.

Ascofuranone demonstrated antitumor activity against FM3A murine mammary carcinoma, implanted in the peritoneal cavity of syngeneic mice, C3H/He. It was more effective by treatment prior to implantation than by that after implantation. Treatment with ascofuranone also increased splenic cytotoxicity and phagocytic activity of host animal cells. Moreover, ascofuranone induced inflammatory cells in the peritoneal cavity which are mainly composed of polymorphonuclear leukocytes and macrophages. These cells are more potent in cytotoxicity against FM3A cells than with resident peritoneal cells. The antitumor activity of ascofuranone was suppressed by ip administration of silica, just prior to tumor implantation. These results suggest that the prophylactic antitumor activity of ascofuranone is expressed through the activation of phagocytes. Ascofuranone also suppressed pulmonary metastasis of B16 melanoma and Lewis lung carcinoma. Treatment after tumor implantation failed to suppress the metastasis. Single treatment of ascofuranone 4 days prior to implantation decreased the metastasis of Lewis lung carcinoma but not that of B16, whereas single treatment of ascofuranone 24 hours prior to the tumor implantation decreased the metastasis of B16 but not that of Lewis lung carcinoma.

Animals↗
PubMed1987

Suppression of hypertriglyceridemia of Ehrlich carcinoma-bearing mice by an antibiotic, ascofuranone.

Ehrlich ascites carcinoma-bearing mice exhibit hypertriglyceridemia. An antitumor antibiotic, ascofuranone, suppressed tumor-induced hypertriglyceridemia when administered i.p. even when no evident antitumor activity was observed without affecting the levels of free fatty acids, phospholipids, cholesterol, glucose, and total protein in plasma. Ascofuranone did not reduce plasma triglycerides of normal mice. Insulin and clofibrate, known modifiers of lipid metabolism, showed no significant suppression. Ascofuranone is also effective on solid tumor-induced hypertriglyceridemia. Another notable change of metabolism affected by tumor-bearing in the early stage where hypertriglyceridemia has not yet fully progressed is hypoglycemia. Although ascofuranone did not affect hypoglycemia, the suppressive effect on hypertriglyceridemia was more evident when ascofuranone was administered in the early stage than in the later stage. These results suggest that ascofuranone suppresses hypertriglyceridemia by specifically affecting the changes of host metabolism which is induced in the early stage of tumor bearing.

Animals↗
PubMed1987

Macrophage-specific effect on lipid metabolism by an antibiotic, ascofuranone.

Ascofuranone (AF) enhanced glucose consumption of splenocytes and macrophages, while it enhanced incorporation of [14C]acetate into macrophages but not into splenocytes. When using tumor cell lines, it inhibited the incorporation of [14C]acetate into lymphoma cell lines, YAC-1 and P388, and a thymoma, L5178Y, while it stimulated that into P388D1, which is derived from P388 and has macrophage-like characteristics. Incorporation of [14C]acetate into a mammary carcinoma FM3A was also stimulated by AF. In contrast, AF stimulated uptake of methylglucose in all cell lines tested. The effect of AF was further studied using mouse myeloid leukemia, M1 cells. AF slightly stimulated the incorporation of [14C]acetate into undifferentiated M1 cells, and strongly stimulated that of hydrocortisone-differentiated M1 cells. In contrast, AF suppressed the incorporation of [14C]acetate into retinoic acid-differentiated M1 cells. Glucose consumption of these three types of M1 cells was all stimulated. From these results, we conclude that AF specifically stimulates the incorporation of [14C]acetate into macrophages while it generally stimulates glucose uptake of the cells.

Acetates↗
PubMed1986

Activation of natural cytotoxic activity and concomitant reduction of triglyceride content of murine spleen, treated with an antitumor antibiotic, ascofuranone.

Ascofuranone (AF) elevated natural cytotoxic activity of spleen when it was administered intraperitoneally to male mice. The elevation was observed both in low and high responder mice. AF-activated splenocytes lysed NK-resistant tumor cells, FM3A, P388 and sarcoma 180 cells as well as NK-sensitive YAC-1 cells. However, AF suppressed other lymphatic functions such as mitogenic responses and interleukin 2 production. Because AF did not activate splenic NK activity in vitro, the activation is assumed to be caused by a host-mediated process. One of the possibilities is modulation of the lipid metabolism of splenocytes. Thus, we examined splenic lipid contents and revealed that AF decreased splenic triglycerides without affecting other lipids. In contrast, the antibiotic significantly increased triglyceride in muscle.

Animals↗
PubMed1986

In vitro effects of an antitumor antibiotic, ascofuranone, on the murine immune system.

Effects of an antitumor antibiotic, ascofuranone (AF) on the murine immune system were studied. Unlike lectins, AF did not induce any proliferative response of splenocytes. Furthermore, AF significantly inhibited proliferative response of splenocytes in response to lectins, such as concanavalin A, lipopolysaccharide, or phytohemagglutinin above 5 micrograms/ml. In concanavalin A-induced T-lymphocyte response, AF selectively inhibited the formation of interleukin 2 (IL-2) receptors, which was observed above 0.4 micrograms/ml. On the other hand, the inhibitory effect on the proliferative response to IL-2 of T-lymphocytes, which had already obtained IL-2 receptors, was observed above 10 micrograms/ml. IL-2 production of splenocytes in response to concanavalin A was also suppressed by AF above 2 micrograms/ml and only 3% of IL-2 was produced in the presence of AF, 10 micrograms/ml. However, AF-activated macrophages and their glycolysis was significantly stimulated. Activation of macrophages by AF was also confirmed by stimulation of interleukin 1 production and tumoricidal activity. However, natural killer activity of splenocytes was suppressed at the concentration where significant activation of tumoricidal activity of macrophages was observed. Therefore, AF had a dual effect on the immune system. Macrophages were activated to produce interleukin 1 and to kill tumor cells. On the other hand, functions of lymphocytes were suppressed.

Animals↗
PubMed1983

Effects of an antitumor agent, ascofuranone, on the macromolecular syntheses of intact cells.

Ascofuranone (AF) has antitumor protective property on experimental tumors. We examined the action of AF on lymphoma L5178Y to explore the mechanism of the antitumor activity. AF completely prevented the growth of L5178Y at 25 micrograms/ml cytostatically. The compound exhibited general inhibitory effects on the macromolecular syntheses. Among them, protein synthesis was most severely inhibited by AF and to the same extent as by cycloheximide. AF, however, did not affect protein synthesis by cell-free system even at 2 mg/ml. Although AF inhibited the incorporation of [14C]acetate into total acid precipitable products only slightly, the synthetic pattern of simple lipids from [14C]acetate was significantly changed. Especially, the incorporation of [14C]acetate into squalene was almost completely blocked at 25 micrograms/ml. The incorporation of [14C]acetate into triglyceride was inhibited and that into cholesterol was enhanced. Concerning the diglycerides, the incorporation of [14C]acetate was enhanced and that of [3H]glycerol was inhibited. The incorporation of [3H]glycerol and [3H]mevalonate into the intact cell was significantly inhibited as compared with [14C]acetate. As those effects were not observed with cycloheximide, they were suggested to be characteristic of AF. AF inhibited hypotonic hemolysis. In contrast, hemolysis by deoxycholate was stimulated. Possible mechanism of the antitumor activity of AF is discussed.

Adult↗