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Biomedical subjects

N Inamura

Publications and source records attributed to N Inamura.

At least 73 records · Page 4Linked to original sources
PubMed1990

Abnormally high expression of proteasomes in human leukemic cells.

Proteasomes are eukaryotic ring-shaped or cylindrical particles with multicatalytic protease activities. To clarify the involvement of proteasomes in tumorigenesis of human blood cells, we compared their expression in human hematopoietic malignant tumor cells with that in normal peripheral blood mononuclear cells. Immunohistochemical staining showed considerably increased concentrations of proteasomes in leukemic cells from the bone marrow of patients with various types of leukemia and the predominant localization of these proteasomes in the nuclei. Moreover, enzyme immunoassay and Northern blot analysis indicated that the concentrations of proteasomes and their mRNA levels were consistently much higher in a variety of malignant human hematopoietic cell lines than in resting peripheral lymphocytes and monocytes from healthy adults. Proteasome expression was also greatly increased in normal blood mononuclear cells during blastogenic transformation induced by phytohemagglutinin; their expression increased in parallel with induction of DNA synthesis and returned to the basal level with progress of the cell cycle. Thus, abnormally high expression of proteasomes may play an important role in transformation and proliferation of blood cells and in specific functions of hematopoietic tumor cells.

Antibodies, Monoclonal↗
PubMed1990

Monoclonal anti-P-glycoprotein antibody-dependent killing of multidrug-resistant tumor cells by human mononuclear cells.

Mouse monoclonal antibodies (MRK16 and MRK17) against human multidrug-resistant cancer cell lines were tested for antibody-dependent cytotoxicity mediated by human blood mononuclear cells, using a 4-h 51Cr release assay. MRK16 (IgG2a isotype) was shown to be more effective than MRK17 (IgG1 isotype). Moreover, when four pairs of drug-resistant and their parent sensitive human cancer cells were tested for antibody-dependent cell-mediated cytolysis (ADCC) using MRK16, only the drug-resistant cell lines were susceptible to ADCC reaction. When highly purified lymphocytes (greater than 99%) and monocytes (greater than 97%) were isolated from blood mononuclear cells by centrifugal elutriation and adherence, MRK16 promoted both lymphocyte- and monocyte-mediated tumor cell killing, whereas MRK17 induced only a lymphocyte-mediated ADCC reaction. These results suggest that MRK16 of IgG2a subtype may be a useful therapeutic agent in eradication of drug-resistant cancer cells expressing P-glycoprotein through ADCC reaction.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Up-regulation by granulocyte-macrophage colony-stimulating factor (GM-CSF) of induction of lymphokine (IL-2)-activated killer (LAK) cells by human blood monocytes.

The role of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) in monocyte-mediated up-regulation of lymphokine-activated killer (LAK) cell induction by IL-2 was examined. Treatment of blood mononuclear cells (MNC) of healthy donors with GM-CSF for 4 days in the presence of IL-2 resulted in a significant increase in LAK activity against natural killer (NK)-resistant Daudi cells, as assessed by the 4 hr 51Cr-release assay. For determination of the role of GM-CSF in LAK induction, highly purified lymphocytes (greater than 99%) and monocytes (greater than 90%) were isolated from MNC by counter-flow centrifugal elutriation (CCE). Pre-treatment of monocytes for 4 days with GM-CSF before addition of lymphocytes plus IL-2 resulted in a significant dose-dependent increase in monocyte-mediated up-regulation of LAK induction, but in the absence of monocytes GM-CSF had no effect on LAK cell induction. Similarly, GM-CSF augmented the proliferative response of lymphocytes to IL-2 in the presence of monocytes as assessed by 3H-TdR uptake. Treatment with anti-GM-CSF antibody completely abolished up-regulation of LAK induction by GM-CSF-treated monocytes. When blood monocytes were separated into 5 fractions by CCE, GM-CSF-responding monocytes were found to be responsible for up-regulation of LAK induction. These results suggest that GM-CSF may be important in monocyte-mediated up-regulation of LAK cell induction in vivo.

Colony-Stimulating Factors↗
PubMed1989

Tumor cytotoxicity of human monocyte membrane-bound interleukin-1 alpha induced by synergistic actions of interferon-gamma and synthetic acyltripeptide, FK-565.

Human blood monocytes were isolated by counter-flow centrifugal elutriation from healthy donors and these noncytotoxic monocytes were rendered tumoricidal to allogeneic melanoma (A375) cells by activation with a synthetic acyltripeptide (FK-565), as assessed by measuring release of [125I]iododeoxyuridine in 72 h. When monocytes were treated with FK-565 for 16 h, and then fixed with paraformaldehyde, they showed cytotoxicity to A375 melanoma cells. The fixed-monocyte-mediated cytotoxicity to A375 cells was induced by the synergistic actions of FK-565 and recombinant interferon-gamma (rIFN-gamma), but not other cytokines [rIFN-alpha A, rIFN-beta, tumor necrosis factor (TNF), interleukin (IL)-2, -3 and -6]. For synergistic activation of monocytes with induction of a membrane-associated antitumor monokine, the monocytes had to be incubated first with rIFN-gamma and then with FK-565. FK-565 also acted synergistically with rIFN-gamma to stimulate monocytes to produce membrane-associated IL-1 activity, which induced C3H/HeJ thymocyte blastogenesis in response to phytohemagglutinin P. The tumoricidal and thymocyte-stimulating activities of the fixed monocytes were almost completely inhibited by a specific anti-(IL-1 alpha) antiserum, but not by a specific anti-(IL-1 beta) antiserum or monoclonal anti-TNF antibody. These results suggest that membrane-associated IL-1 alpha of human blood monocytes can be induced by two activation signals (rIFN-gamma then FK-565) at their suboptimal concentrations.

Antineoplastic Agents↗
PubMed1989

Killing of alveolar macrophages and of monocytes that have responded to granulocyte-macrophage colony-stimulating factor by human lymphokine-activated killer cells.

The susceptibilities of human blood monocytes and alveolar macrophages (AM) to cytotoxicity mediated by lymphokine (IL-2)-activated killer (LAK) cells were examined. Monocytes and AM of healthy donors were obtained by counter-flow centrifugal elutriation (CCE) and bronchoalveolar lavage, respectively. The LAK activity induced by incubation of blood mononuclear cells (MNC) for 4 days with recombinant interleukin 2 (IL-2) was measured by a 4-h 51Cr release assay. The LAK cells were not cytotoxic to freshly isolated monocytes, but were cytotoxic to autologous fresh AM and monocytes that had been incubated for more than 4 days in medium alone. Blood monocytes that had been incubated for 4 days in medium with granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF) or interleukin 3(IL-3) were much more susceptible than untreated monocytes to the cytotoxicity of LAK cells. When blood monocytes were separated by CCE into subpopulations of three sizes (small, medium and large), the medium- and large-sized monocytes showed greater responses to GM-CSF in terms of DNA synthesis and colony formation than the small-sized cells. After treatment with GM-CSF for 4 days, these medium and large monocytes were more susceptible than the small monocytes to the cytotoxic action of LAK cells. These results suggest that LAK cells may be important in situ in down-regulating the functions of mature macrophages and blood monocytes that have responded to GM-CSF.

Biological Factors↗
PubMed1989

Induction of membrane-associated interleukin 1 alpha (IL-1 alpha) by synergistic activation of human blood monocytes with interferon gamma and muramyl dipeptide analog.

Human blood monocytes isolated by centrifugal elutriation from healthy donors were tested for ability to produce membrane-associated IL-1 in response to activation stimuli such as various types of interferons (alpha, beta and gamma) and/or synthetic des-methyl muramyl dipeptide (norMDP). When monocytes were treated with norMDP or lipopolysaccharide (LPS) for 16 hr, they released IL-1 into their culture supernatant. When these activated monocytes were fixed with paraformaldehyde (PFA), they stimulated blastogenic responses of C3H/HeJ mouse thymocytes to PHA, suggesting that membrane-associated IL-1 could be induced by norMDP or LPS. Membrane-associated IL-1 was also found to be induced by the synergistic actions of suboptimal concentrations of rIFN-gamma and nor MDP, but not of rIFN-alpha A or rIFN-beta with norMDP. A specific anti-IL-1 alpha antiserum completely inhibited membrane-associated IL-1 activity, but did not affect the thymocyte-stimulating activity of fixed monocytes. IL-1 alpha was detected by fluorescence staining using the anti-IL-1 alpha antiserum on monocytes fixed after gamma IFN-gamma and norMDP. These results suggest that IFN-gamma may be important in expression of membrane-bound IL-1 alpha by the human blood monocytes responsible for regulation of immune responses in vivo.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1989

[In vivo effect of etoposide on the function of bone marrow-derived macrophages].

Proliferative and colony-forming abilities of bone marrow cells to M-CSF and the function of the bone marrow-derived macrophages were examined 2, 7, 14 and 21 days after intraperitoneal injection of etoposide. Only two days after administration of etoposide (50 mg/kg of body weight), the number of bone marrow cells per femur was significantly decreased, but completely recovered by day 7. In contrast, proliferative and colony-forming responses of the bone marrow cells to M-CSF was increased after 2 days, but there-after returned to the normal. The abilities of bone marrow-derived macrophages to adhere to plastics and to produce monokines (IL-1 and TNF) were the same as those of controls before and after treatment with etoposide. These data suggest that activation of macrophage progenitors in bone marrow may be useful in combination with chemotherapy for treatment of malignant diseases.

Animals↗
PubMed1988

Heterogeneity of human lymphokine (IL-2)-activated killer (LAK) precursors and regulation of their LAK induction by blood monocytes.

Highly purified lymphocytes (greater than 99%) and monocytes (greater than 90%) were isolated by CCE from peripheral blood of healthy donors. Blood lymphocytes were separated by this CCE into 9 subpopulations. The NK activities of these lymphocyte fractions against NK-sensitive K-562 cells and their LAK activities against NK cell-resistant target (Daudi) cells were assayed promptly or after incubation of the fractions for 4 days with or without an optimal concentration of IL-2. NK and LAK activities were measured by 4-hr 51Cr-release assay. On the basis of their NK and LAK activities, these lymphocyte fractions were classified into 3 subpopulations of LAK precursors: one lacking both NK and LAK activities (Fr.2), one with moderate NK activity but low LAK activity (Fr.5), and one possessing both NK and LAK activities (Fr.8). Addition of autologous fresh monocytes to the lymphocyte cultures resulted in a significant increase in induction of LAK activity in Fr.2 and Fr.5. This up-regulation of lymphocytes in Fr. 2 and Fr.5 by monocytes was confirmed in parallel experiments by measuring the blastogenic response of the lymphocytes to IL-2. Deletion of lymphocytes in Fr. 8 of CD16+ (Leu-11+) NK cells resulted in 74% reduction in LAK induction, whereas depletion of mixtures of monocytes and lymphocytes in Fr. 2 of cells reacting with CD3+ (OKT3+) antibody resulted in a 66% reduction in LAK induction. This up-regulation of LAK cell induction from LAK precursors by monocytes was confirmed using 4 lines of human lung cancer cells as targets for LAK activity. These results clearly indicate that human monocytes may cause up-regulation of the expression of IL-2-induced LAK activity in T cells and in a subpopulation of NK cells.

Centrifugation, Density Gradient↗
PubMed1988

Synergism of synthetic acyltripeptide and its analogs with recombinant interferon gamma for activation of antitumor properties of human blood monocytes.

Human blood monocytes freshly isolated by centrifugal elutriation from healthy volunteers were not cytotoxic to allogeneic A375 melanoma cells, but they were activated to the tumoricidal state by incubation in vitro with FK-565, (heptanoyl-gamma-D-Glu-(L)-meso-alpha,epsilon-A2pm(L)-D-A laOH), which is a synthetic acyltripeptide closely resembling cell wall peptidoglycan peptides of Streptomyces in structure. Among 11 different derivatives of FK-565, 7 analogs were more potent activators of monocytes for tumor cell killing than FK-565. The maximal expression of tumoricidal monocytes was dependent on the concentration of FK-565 or its analogs added and the ratio of monocytes to target tumor cells. In a parallel experiment, a combination of a subthreshold concentration of FK-565 or its analogs (FR-42148 and FR-42149) and recombinant interferon gamma (rIFN-gamma) induced significant monocyte-mediated tumorcell killing, indicating that the effects of rIFN-gamma and acyltripeptide or its analogs in monocyte activation are synergistic. In contrast to rIFN-gamma, recombinant rIFN-alpha A and rIFN-beta had additive effects with acyltripeptide or its analogs in human monocyte activation. These results suggested that synthetic acyltripeptide and its analogs combined with rIFN-gamma could be of clinical value for in situ activation of the tumoricidal activity of human blood monocytes responsible for eradication of cancer metastases.

Adjuvants, Immunologic↗
PubMed1988

Immunosuppressive effect of FK506 on collagen-induced arthritis in rats.

FK506, a new immunosuppressive agent, was given intramuscularly to rats for 12 days, starting on the day of type II collagen immunization. FK506 in doses of 0.32 mg/kg or more suppressed arthritis and also suppressed humoral and skin test response to type II collagen. FK506 suppressed arthritis only when given during the afferent limbs of immune response (0-4 days), whereas the drug was only marginally effective when treatment was started during the efferent limbs of immune response (7-11 days). FK506-induced immunosuppression continued and/or was maintained throughout the experiments (50 days). These rats immunized with type II collagen and treated with FK506 failed to develop arthritis even following a secondary immunization 50 days later but were fully capable of developing experimental allergic encephalomyelitis. This result suggest that FK506-treated rats develop specific unresponsiveness toward the type II collagen. It is concluded that FK506 is a strong immunosuppressive drug on collagen-induced arthritis.

Animals↗
PubMed1988

Immunosuppressive effect of FK506 on experimental allergic encephalomyelitis in rats.

We investigated the effect of a new immunosuppressant, FK506, on the development of experimental allergic encephalomyelitis (EAE) in rats. EAE developed in 100% of rats immunized with myelin basic protein (MBP) in complete Freund's adjuvant. FK506 in doses of 1.0 mg/kg/day or more prevented the clinical signs of EAE for at least 50 days, when administered intramuscularly 5 days a week for 2 weeks starting on the day of immunization (days 0-4 and days 7-11), and a similar result was obtained, when the compound was given for 5 days (days 0-4). FK506, however, showed a significant but weak effectiveness when started from 7 days after immunization. Delayed-type hypersensitivity (DTH) to MBP developed before EAE, and anti-MBP antibody levels increased. Both humoral and cellular immune response to MBP were completely suppressed in rats treated with FK506. From these results, it is presumed that immunosuppression of cell-mediated immunity and/or humoral immunity by the treatment of FK506 actually causes the decreased incidence noted in the experiment for the development of EAE.

Animals↗
PubMed1988

Effect of Nocardia rubra cell wall skeleton on interleukin 1 production from mouse peritoneal macrophages.

Nocardia rubra cell wall skeleton (N-CWS) was shown to augment interleukin 1 (IL-1) production from peritoneal resident and exudate macrophages in C3H/HeN mice. The mol. wt of the N-CWS-induced IL-1 product was about 17,000 daltons, which is a similar weight to that obtained by lipopolysaccharide stimulation. The stimulation of IL-1 production by N-CWS was seen as early as 8 h after the start of incubation and peak production was observed at 48 h. Profound effects were seen with 10 micrograms/ml or more of N-CWS. Experiments on the regulation of the N-CWS-augmented IL-1 production showed that prostaglandin E2 inhibited the augmentation, and indomethacin (cyclo-oxygenase inhibitor) further augmented it. Leukotriene B4 and AA861 (lipoxygenase inhibitor) had no effect. Our findings suggest that the previously reported adjuvant effect of N-CWS may, in part, be mediated via its ability to stimulate IL-1 production; and that such a stimulation may be blocked by prostaglandins.

Animals↗
PubMed1988

Prolongation of skin allograft survival in rats by a novel immunosuppressive agent, FK506.

FK506, an immunosuppresant, was isolated from Streptomyces tsukubaensis. Intramuscular administration of FK506 (0.32 mg/kg or more) 5 days a week for two weeks after grafting prolonged the acceptance time of F344 skin allograft to WKA rats. Similar results were obtained with cyclosporine at 32 mg/kg or more, but other immunosuppressives (i.e., prednisolone, azathioprine, and bredinin) gave only a marginal prolongation. The prolonging effect of FK506 was obtained in various donor-recipient combinations across a major or minor histocompatibility barrier. The agent also prolonged the acceptance time of mouse skin xenografts to rats. Furthermore, maintenance doses of 3.2 or 0.32 mg/kg twice a week after an initial 14-day treatment with the agent at 3.2 mg/kg gave graft survival as long as the treatment was continued for more than 120 days. Our findings show that FK506 has a potent immunosuppressive effect in rats and suggest that the agent merits further investigation.

Animals↗
PubMed1988

FR-900520 and FR-900523, novel immunosuppressants isolated from a Streptomyces. II. Fermentation, isolation and physico-chemical and biological characteristics.

FR-900520 and FR-900523, novel neutral macrolide immunosuppressants, were isolated from the cultured broth of Streptomyces hygroscopicus subsp. yakushimaensis No. 7238. Their molecular formulae were determined as C43H69NO12 and C42H67NO12, respectively. The compounds suppressed immune response in vitro. IC50 values of FR-900520 and FR-900523 for mouse mixed lymphocyte reaction were 0.55 nM and 1.6 nM, respectively. FR-900520, the major component, clearly prolonged skin allograft survival in rats.

Animals↗
PubMed1987

Pathophysiology and prognosis of sudden deafness with special reference to the N1 latency.

Electrocochleography (ECochG) was performed in 84 patients with sudden deafness which were classified into 3 groups according to the ECochG findings, i.e. the unchanged N1 latency, the prolonged N1 latency and the absence of N1 response. The cause of hearing loss in the first group was thought to be strial, postsynaptic or mild cochlear damage and that in the second to be vascular, sensory or neural damage. The first group showed a better prognosis than those of the other two.

Adolescent↗
PubMed1987

Effect of hypothermia on the cochlear potentials.

The effects of hypothermia upon the cochlear potentials were studied in 30 guinea pigs. Particular attention was paid to the transient increase in AP amplitude at a moderate temperature. CM and AP were recorded via an Ag-AgCl lead placed on the round window membrane. Although the CM amplitude and threshold, and the AP latency and threshold were both impaired concomitant with the lowering of body temperature, the AP amplitude exhibited a transient increase at the beginning of cooling (peak at 30 degrees C) and a decrease thereafter. Narrow-band analysis of AP revealed that this phenomenon was most prominent in the high-frequency region. When the cochlear efferent fibers (crossed and uncrossed olivocochlear bundle) were cut, this transient increase in AP amplitude disappeared. This phenomenon seems to be due to the difference in sensitivity to hypothermia between the efferent and afferent fiber systems.

Action Potentials↗
PubMed1987

Cochlear potentials of guinea pigs with experimentally induced renal failure.

In order to investigate the relationship between renal failure and hearing loss, the authors made a guinea pig model with experimentally induced renal failure and examined cochlear potentials (N1, CM and EP). When renal damage was greater, the amplitudes of N1 and CM were decreased and the latency of N1 was prolonged, but EP was within normal range. The sensory cells of the cochlea were considered responsible for the hearing loss in the guinea pig model. No pathological alterations of the cochlea were revealed by a light microscopy. It is suggested that the etiology of the hearing loss was due mainly to metabolic disturbances such as uremic toxins, electrolyte imbalance or endocrine abnormalities.

Acute Kidney Injury↗