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Biomedical subjects

K Motoyoshi

Publications and source records attributed to K Motoyoshi.

At least 91 records · Page 5Linked to original sources
PubMed1997

Differanisole A, a novel antitumor antibiotic, enhances growth inhibition and differentiation of human myeloid leukemia cells induced by 9-cis retinoic acid.

Differanisole A, 3,5-dichloro-2-hydroxy-4-methoxy-6-n-propylbenzoic acid, inhibited growth of human myeloid leukemia cells. The compound induced G1 arrest and granulocytic differentiation of HL-60 cells, although the differentiation-inducing effect was modest. Differanisole A and 9-cis retinoic acid (9cisRA) synergistically inhibited the growth and induced functional and morphologic differentiation of HL-60 and NB4 cells, whereas the combined treatment with differanisole A and all-trans retinoic acid or 1alpha,25-dihydroxyvitamin D3 was less effective. Similar results were obtained in primary culture of leukemia cells from a patient with acute promyelocytic leukemia. The synergistic effect on growth inhibition and induction of differentiation required simultaneous treatment with differanisole A and 9cisRA. Differanisole A and an RXR-specific ligand (Ro47-5944) cooperatively inhibited the cell growth, while the combined effect of differanisole A and an RAR-specific ligand Am80 was just additive. Differanisole A in combination with 9cisRA may have implications for therapy of acute promyelocytic leukemia patients.

Alitretinoin↗
PubMed1997

Biologic activity of proteoglycan macrophage colony-stimulating factor.

We compared the biologic activities of 85-kDa macrophage-CSF (85-kDa M-CSF), which is fully active, and a proteoglycan M-CSF (PG-M-CSF). Both originate from the same precursor, but the latter retains the carboxyl-terminal portion, which must be proteolytically removed from the precursor to generate 85-kDa M-CSF and which is uniquely modified by a chondroitin sulfate glycosaminoglycan chain. PG-M-CSF supported the formation of murine macrophage colonies such as 85-kDa M-CSF. Furthermore, PG-M-CSF stimulated the proliferation of murine bone marrow macrophages, an M-CSF-dependent murine cell line, and an M-CSF-responsive human cell line established by transfer of the human M-CSF receptor gene. PG-M-CSF and 85-kDa M-CSF had equivalent specific biologic activities on a molar basis in all bioassays. The activity of PG-M-CSF was not affected by enzymatically removing the glycosaminoglycan chain when assayed by the formation of macrophage colonies and proliferation of the bone marrow macrophages. We analyzed the phosphorylation on tyrosine residue(s) of the M-CSF receptor in response to these M-CSFs that trigger mitogenic responses. PG-M-CSF rapidly (within 10 min) induced receptor phosphorylation in human cells with the same potency as 85-kDa M-CSF. These results indicate that PG-M-CSF is not a latent form or precursor of 85-kDa M-CSF but a fully biologically active cytokine.

Animals↗
PubMed1997

Identification of binding domains for basic fibroblast growth factor in proteoglycan macrophage colony-stimulating factor.

We recently demonstrated that proteoglycan macrophage colony-stimulating factor (PG-M-CSF) binds basic fibroblast growth factor (bFGF) and neutralizes the biological activity of bFGF. In this study, we identified the binding sites of PG-M-CSF for bFGF. We examined the binding of bFGF to overlapping 12-mer peptides with the sequence of the putative binding region. High affinity binding was detected at two peaks; one consisted of the three adjacent peptides, 212-223, 213-224 and 214-225 and the other, of the three adjacent peptides, 246-257, 247-258 and 248-259. The synthetic peptide (212VDPGSAKQRPPRST225) did not inhibit bFGF binding to another peptide (246PQPRPSVGAFNPGM259), and vice versa. However, both peptides inhibited the bFGF-induced but not platelet-derived growth factor-induced stimulation of DNA synthesis in murine Balb/c 3T3 cells.

3T3 Cells↗
PubMed1997

Enhancement of macrophage colony-stimulating factor-induced growth and differentiation of human monocytes by interleukin-10.

Interleukin-10 (IL-10) has been reported to be a negative cytokine for monocytes/macrophages. In the present study, we showed that IL-10 is rather a positive cytokine and augments the growth and differentiation of human monocytes stimulated with macrophage colony-stimulating factor (M-CSF). Highly purified adherent human monocytes were cultured for 7 days with M-CSF in the presence or absence of IL-10. The number of recovered cells increased in the culture of monocytes with M-CSF + IL-10 compared to the culture with M-CSF alone. IL-10 alone was not enough to maintain the survival and differentiation of monocytes into macrophages. Morphological change cultured in M-CSF was also accelerated by addition of IL-10, and macrophages cultured in M-CSF + IL-10 were more elongated compared to macrophages cultured with M-CSF alone. Binding of 125I-M-CSF to monocytes incubated with M-CSF + IL-10 was about 1.7-fold higher than that to monocytes incubated with M-CSF alone. In accordance with the binding study, Northern blot analysis showed that the levels of the expression of c-fms, M-CSF receptor, mRNA in macrophages cultured in M-CSF + IL-10 were higher than that in macrophages cultured in M-CSF alone. Macrophages cultured in M-CSF + IL-10 expressed higher level of Fc gamma RI, II, III, and showed augmented Fc gamma receptor mediated phagocytosis. The former also produced higher level of H2O2 and O2-, when stimulated with zymosan, and of IL-6 when stimulated with lipopolysaccharide compared to the latter. These results taken together suggest that IL-10 augments the growth and differentiation of human monocytes cultured in M-CSF.

Antigens, Surface↗
PubMed1997

Properties of primary murine stroma induced by macrophage colony-stimulating factor.

The ability of purified human macrophage colony-stimulating factor (M-CSF) to accelerate the formation of stromal cells from murine bone marrow cells was investigated. The liquid culture of the marrow cells with M-CSF resulted in the formation of monolayers of macrophages on day 7. When the M-CSF was removed on that day and the residual adherent cells were cultured in the absence of M-CSF for an additional 7 days, many colonies appeared with cells that were morphologically distinguishable from M-CSF-derived macrophages. The appearance of the colonies was dependent on the concentration of M-CSF used at the beginning of the culture. Each colony was isolated as a single clone and analyzed. All clones were negative for esterase staining. These cells did not express M-CSF receptor mRNA and did not show a mitogenic response to M-CSF. On the contrary, these cells could be stimulated to proliferate by fibroblast growth factor and platelet-derived growth factor. The polymerase chain reaction analysis of these cells demonstrated constitutive expression of mRNA for M-CSF, stem cell factor, and interleukin (IL)-1, but not IL-3. Some clones expressed mRNA for granulocyte/M-CSF and IL-6. We also examined the ability of the cells to maintain murine bone marrow high proliferative potential colony-forming cells (HPP-CFC) in a coculture system. Most of the clones showed a significant increase in total HPP-CFC numbers after 2 weeks of coculture, although the extent of stimulation differed among clones. These results suggested that the colonies established by M-CSF were composed of functional stromal cells that were phenotypically different from macrophages.

Animals↗
PubMed1997

Antimetastatic effect of recombinant human macrophage-colony-stimulating factor against lung and liver metastatic B16 melanoma.

We studied the effect of recombinant human macrophage-colony-stimulating factor (rhM-CSF) on the formation of lung and liver metastases following the i.v. injection of the B16 melanoma subline (B16 LiLu) into mice. When rhM-CSF was administered before the B16 inoculation, the number of tumor metastases decreased in the lung and liver. However, the administration of rhM-CSF after B16 inoculation did not produce an antimetastatic effect in the lung, but did in the liver, B16 cells labeled with 5-[125I]-iodo-2'-deoxyuridine (125I-dUrd) were injected and the arrest of tumor cell emboli was examined in the capillary beds of the lung and liver of mice treated with either vehicle or rhM-CSF. In both groups, there were the same numbers of B16 cells in both the lung and the liver 3 minutes after the B16 injection, and almost all tumor cells died within 24 h. However, the number of cells surviving in the lung was decreased in mice injected with rhM-CSF (37%). There was no difference in the number of cells in the livers of mice treated either with vehicle or rhM-CSF in the first 24 h after tumor cell injection. The administration of rhM-CSF increased NK 1.1+ cells in the mouse spleen and facilitated NK activity in vivo. At the same time, the administration of an anti-NK 1.1 antibody blocked the antimetastatic effect of rhM-CSF in the lung but not in the liver. The antibody was effective only when it was injected before the B16 inoculation. These results suggest that the antimetastatic effect of rhM-CSF in the lung was mediated by NK 1.1+ cells within 24 h of B16 injection. In contrast, the antimetastatic effect of rhM-CSF in the liver was mediated not only by NK 1.1+ cells but also by other antimetastatic systems such as macrophages.

Animals↗
PubMed1997

Human urinary macrophage colony-stimulating factor reduces the incidence and duration of febrile neutropenia and shortens the period required to finish three courses of intensive consolidation therapy in acute myeloid leukemia: a double-blind controlled study.

PURPOSE: To determine whether macrophage colony-stimulating factor (M-CSF) reduces the incidence and duration of febrile neutropenia during three courses of intensive consolidation therapy and whether it shortens time to complete consolidation therapy. PATIENTS AND METHODS: In 198 adult patients with acute myeloid leukemia (AML) in complete remission (CR), M-CSF (8 x 10(6) U/d) or placebo was administered from 1 day after the end of each consolidation chemotherapy for 14 days. RESULTS: The duration and incidence of febrile neutropenia was significantly reduced by 34% (P = .00285) and 17% (P = .02065), respectively, in 88 assessable patients in the M-CSF group compared with those in 94 assessable patients in the placebo group. Patients in the M-CSF group had 565 days and 133 episodes of febrile neutropenia during 7,901 days at risk, while patients in the placebo group had 977 days and 185 episodes during 9,077 days at risk. The median period required to finish the three courses of consolidation therapy was 93 days in the M-CSF group, which was significantly shorter than 110 days in placebo group (P = .0050). In the M-CSF group, the recovery of neutrophils and platelets was significantly faster (P = .0348 and P = 0.0364, respectively), the administration of systemic antimicrobial agents tended to be less (P = .0839), and the frequency of platelet transfusion (P = .0259) and the total volume of transfused platelets (P = .0292) were significantly less. However, there was no significant difference in the disease-free survival. CONCLUSION: M-CSF significantly reduced the incidence and duration of febrile neutropenia during the intensive consolidation therapy, and shortened the time to complete consolidation chemotherapy in AML.

Acute Disease↗
PubMed1996

Tumor vaccination with macrophage colony-stimulating factor-producing Lewis lung carcinoma in mice.

Expression of various cytokines by cytokine gene-transduced tumor cells has been shown to increase antitumor immunity of tumor-bearing hosts. In the present study, macrophage-colony stimulating factor (M-CSF) cDNA was retrovirally transfected into Lewis lung carcinoma cells (3LL) of C57BL/6 mouse origin, and the effects of M-CSF expression were studied by inoculating syngeneic C57BL/6 mice with M-CSF-expressing 3LL cells. The mice inoculated with the lowest M-CSF-producing 3LL clone showed significant prolongation of the survival compared with wild-type 3LL-Inoculated mice, and 70% or more of the mice inoculated with 3LL clones with higher M-CSF production rejected inoculation. Mice injected with radiation-inactivated M-CSF-expressing 3LL cells before or after Inoculation of wild-type 3LL cells showed prolonged survival compared with mice injected with radiated control 3LL cells before or after transplantation of wild-type cells. In vivo depletion of effector subpopulations by injection of antibodies against CD4+ T cells, CD8+ T cells, or natural killer (NK) cells suggested involvement of NK cells and CD4+ T cells in M-CSF-mediated antitumor cytotoxicity in M-CSF-producing 3LL cells-inoculated mice. Severe combined immunodeficiency (SCID) mice with defective T- and B-cell function showed prolonged survival duration after inoculation with M-CSF-expressing 3LL cells compared with those transplanted with control 3LL cells, and this effect of M-CSF expression by 3LL-cells in SCID mice was also abolished by in vivo depletion of NK cells by antibody injection. These findings together with the previous reports that M-CSF augments antibody-dependent and-independent antitumor cytotoxicity suggest that M-CSF induces tumor immunity in this cytokine-expressing tumor-transplantation model.

Animals↗
PubMed1996

Recombinant human macrophage-colony stimulating factor suppresses the mouse mixed lymphocyte reaction.

We examined the effect of recombinant human macrophage-colony stimulating factor (rhM-CSF) on mouse macrophage accessory functions in vitro. The addition of rhM-CSF to an allogenic mixed lymphocyte culture (MLC) consisting of mouse spleen cells suppressed the proliferation of lymphocytes in a concentration-dependent manner. However, rhM-CSF did not suppress the mixed lymphocyte reaction (MLR) on the MLC that contained only purified T and dendritic cells. This suggested that the suppressive effect of rhM-CSF on the MLR occurs via spleen macrophages. Suppression of the MLR by rhM-CSF could not be neutralized by the addition of synthetic inhibitors of prostaglandin E2 (indomethacin) and nitric oxide (NG-mono-methyl-L-arginine). An antibody specific to mouse interleukin-10 (IL-10), which can neutralize the inhibitory effect of recombinant IL-10 in vitro, did not prevent rhM-CSF-induced suppression of the MLR. Even higher concentrations of IL-1 could not overcome the inhibitory effect of rhM-CSF. Moreover, culture supernatants of macrophages stimulated with rhM-CSF had a suppressive effect on the MLR. The concentrations of transforming growth factor beta (TGF-beta) and IL-10 in the suppressive culture supernatants were lower than those in the supernatants of nonstimulated macrophages. The supernatants suppressed the proliferation of the LBRM 33 TG6 mouse T cell line, but it did not affect the proliferation of other cell lines (L1210, L5178Y-R, and MC/9). These results suggest that rhM-CSF modulates a macrophage accessory function by stimulating macrophages to secrete a suppressive factor that causes suppression of the T cell response in vitro.

Animals↗
PubMed1996

Fas ligand in human serum.

The Fas ligand (FasL), a member of the tumor necrosis factor family, induces apoptosis in Fas-bearing cells. The membrane-bound human FasL was found to be converted to a soluble form (sFasL) by the action of a matrix metalloproteinase-like enzyme. Two neutralizing monoclonal anti-human FasL antibodies were identified, and an enzyme-linked immunosorbent assay (ELISA) for sFasL in human sera was established. Sera from healthy persons did not contain a detectable level of sFasL, whereas those from patients with large granular lymphocytic (LGL) leukemia and natural killer (NK) cell lymphoma did. These malignant cells constitutively expressed FasL, whereas peripheral NK cells from healthy persons expressed FasL only on activation. These results suggested that the systemic tissue damage seen in most patients with LGL leukemia and NK-type lymphoma is due to sFasL produced by these malignant cells. Neutralizing anti-FasL antibodies or matrix metalloproteinase inhibitors may be of use in modulating such tissue damage.

Animals↗
PubMed1996

Cyclic change of cytokines in a patient with cyclic thrombocytopenia.

The serial change of various cytokines in the serum from a patient with cyclic thrombocytopenia is described. Interleukin 7, stem cell factor, and transforming growth factor beta 1 synchronized with the platelet count, and there was a significant positive correlation between the three cytokines and the platelet count. Levels of macrophage colony-stimulating factor, thrombopoietin, platelet-associated IgG and erythropoietin changed reciprocally with the platelet count, and there was a significant negative correlation between the platelet count and these cytokines except erythropoietin. No cyclic change was observed in IL-3, IL-6, IL-11, granulocyte-macrophage colony-stimulating factor, or leukaemia inhibitory factor. These observations suggest that this disease involves two cyclic changes: megakaryocytopoiesis and platelet destruction, in both of which the cytokines play an important role.

Adult↗
PubMed1996

An aggressive nasal lymphoma accompanied by high levels of soluble Fas ligand.

Fas ligand (FasL), either in the membrane bound form or soluble form, has cytotoxic activity against Fas-expressing cells. We report a case of nasal lymphoma accompanied by liver damage and pancytopenia. The serum level of soluble FasL (sFasL) was very high on admission, but rapidly decreased to normal levels after chemotherapy for lymphoma. Liver damage and pancytopenia also improved with the decrease in serum sFasL. Since Fas is expressed on both hepatocytes and haemopoietic cells, these facts suggest that FasL was expressed on lymphoma cells and directly associated with pathogenesis of liver damage and pancytopenia through its cytotoxic activity.

Enzyme-Linked Immunosorbent Assay↗
PubMed1996

Phenotypic change and proliferation of murine Kupffer cells by colony-stimulating factors.

Kupffer cells were isolated from C57BL/6 mice by collagenase perfusion and assessed for response to colony-stimulating factors (CSFs) in terms of their phenotypic change and proliferation. Kupffer cells expressed F4/80, but not Mac-1, CD71, or asialo-GM1 initially. This phenotype pattern was different from that of alveolar and peritoneal macrophages. After stimulation with recombinant human macrophage CSF (M-CSF) or mouse granulocyte-macrophage CSF (GM-CSF), Kupffer cells expressed Mac-1 and a low level of CD71 in addition to F4/80 and increased in phagocytotic activity in association with the expression of CR3. Both M-CSF and GM-CSF, but not human IL-3, induced the proliferation of Kupffer cells in a dose-dependent manner, and after 7 days, the number of the cells increased to about four to six times the initial number. The relatively high dose of GM-CSF downmodulated the M-CSF receptor on Kupffer cells and inhibited the cell proliferation induced by the optimal dose of M-CSF. These data indicated that murine Kupffer cells have a different phenotype from other macrophages and that they respond to M-CSF and GM-CSF, leading to functional maturation and proliferation.

Animals↗
PubMed1996

Binding of macrophage colony-stimulating factor to serum proteins.

Although three molecular forms of macrophage colony-stimulating factor (M-CSF) have been reported, Western blot analysis of immunoaffinity-purified M-CSF from human blood has shown that the major species of M-CSF in the serum has a molecular weight (MW) of 85 kD. Superose-12 gel filtration chromatography of immunoaffinity-purified serum M-CSF showed the presence of M-CSF-positive fraction in a higher MW area compared with the elution profile of recombinant human (rh) 85-kD M-CSF. Western blot analysis of the higher MW fraction showed that the M-CSF was the same as rh 85-kD M-CSF (not proteoglycan form of M-CSF), indicating that, in the serum, M-CSF exists bound to some serum proteins. To detect the serum proteins, we performed M-CSF-bound column chromatography. The eluate contained at least three serum proteins including albumin and IgG. This result was supported by chromatography using biotinylated M-CSF and avidin-agarose. The binding between rhM-CSF and albumin or IgG was also demonstrated by high-performance liquid chromatography (HPLC) fractionation of the mixture and enzyme-linked immunosorbent assay (ELISA) of the fractions. In the serum, a fraction of M-CSF seems to be complexed with serum proteins such as albumin and IgG.

Animals↗