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Biomedical subjects

H Nagumo

Publications and source records attributed to H Nagumo.

At least 19 recordsLinked to original sources
PubMed2002

IL-10 enhances B-cell IgE synthesis by promoting differentiation into plasma cells, a process that is inhibited by CD27/CD70 interaction.

Interleukin-10 (IL-10) is a major regulatory cytokine of inflammatory responses that is considered to play an important role in specific immunotherapy. However, whether IL-10 enhances or inhibits B-cell IgE production has remained a matter of contention. To clarify the effect of IL-10 on IgE synthesis in the presence of IL-4 and CD40 signalling, we examined B-cell proliferation, germline epsilon transcripts and plasma cell differentiation. In addition, the effect of CD27 signalling on IgE synthesis in the presence of IL-10, IL-4 and CD40 signalling was investigated. IL-10 facilitated the production of IgE in mononuclear cells and highly purified B-cells, enhanced B-cell proliferation and, most importantly, promoted the generation of plasma cells. However, IL-10 did not enhance expression of germline epsilon transcripts. The addition of CD27 signalling through the use of CD32-CD27 ligand (CD70) double transfectants significantly diminished the B-cell proliferation, IgE synthesis and plasma cell differentiation enhanced by IL-10. IL-10 enhances B-cell IgE production by promoting differentiation into plasma cells. CD27/CD70 interactions under IL-10 and sufficient CD40 cosignalling exert the opposite effect on IgE synthesis. The results of this study indicate that precautions are critical when planning immunotherapy using IL-10 in IgE-related allergic diseases.

Adult↗
PubMed2001

Rho-associated kinase phosphorylates MARCKS in human neuronal cells.

Myristoylated alanine-rich C kinase substrate (MARCKS) is a filamentous actin bundling protein and has multiple sites for phosphorylation, by which the biochemical function is negatively regulated. However, the role of such phosphorylation in physiological functions, particularly in neuronal functions, is not well understood. Using a phosphorylation-site specific antibody, we detected the phosphorylation of MARCKS at Ser159 by various protein kinases. Rho-kinase, protein kinase A, and protein kinase C, could introduce (32)P into human recombinant MARCKS in vitro and the phosphorylation site was confirmed to be the Ser159 residue. In human neuronal teratoma (NT-2) cells, lysophosphatidic acid (LPA) induced MARCKS phosphorylation dose- and time-dependently. This phosphorylation was sensitive to Rho-kinase inhibitor HA1077. However, the phosphorylation induced by PDBu was lesser sensitive. In a skinned NTera-2 cell system, Ca(2+)-independent and GTP gamma S/ATP-stimulated phosphorylation at Ser159 was also sensitive to pre-treatment C3 toxin and HA1077. These findings suggest that the Ser159 residue of MARCKS is a target of LPA-stimulated Rho-kinase in neuronal cells.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2001

Complete arrest from pro- to pre-B cells in a case of B cell-negative severe combined immunodeficiency (SCID) without recombinase activating gene (RAG) mutations.

The B-cell lineage in a patient with B-cell-negative severe combined immunodeficiency (SCID) was analysed by using antisurrogate light chain (SL) MoAbs. Peripheral CD3(+) T cells and CD19(+) B cells were absent in the patient. The common gamma (gamma c) chain was expressed normally on the patient's peripheral NK cells and his peripheral mononuclear cells did not possess any mutations in recombinase activating gene (RAG)-1, 2. Normal levels of expression of Ku70 and Ku80 protein were found by Western blot analysis. The patient did, however, display an increase in fibroblast sensitivity to irradiation. Furthermore, flow cytometric analyses of bone marrow cells showed that surface IgM and cytoplasmic mu positive cells were absent and that CD19(+) B cells were composed of only CD34(+) terminal deoxynucleotidyl transferase (TdT)(+) SL(+) pro-B cells. The complete arrest of pro- to pre-B cell development in the SCID patient's bone marrow suggests that some genes involved in V(D)J recombination, excepting the RAG gene, may play a causative role in the immunodeficiency.

Antigens, CD↗
PubMed2001

[Effect of G-CSF (nartograstim) on neutropenia (leukopenia) induced by taxane in metastatic breast cancer--time-course changes in neutrophil and leukocyte counts].

Since 1997, we have used docetaxel and paclitaxel as the second-line and third-line chemotherapies against anthracycline-resistant metastatic breast cancer. However, these taxane compounds induced neutropenia and leukopenia, which may be reversed by G-CSF (Nartograstim). We thus examined the therapeutic efficacy of nartograstim for time-course changes in neutrophil and leukocyte counts in these patients. No difference was observed in neutrophil or leukocyte count whether the patient was treated with docetaxel or paclitaxel. Neutrophil and leukocyte counts reached a nadir on days 7 to 8 after administration. With a 5-6 day administration of nartograstim, neutrophil or leukocyte counts recovered by the second or third day after the nadir, indicating that the chemotherapy was given safely with nartograstim. In these same patients receiving a given treatment cycle, the number of days until reaching the nadir were almost identical for neutrophils and leukocytes; however, the duration of the nadir and the time to count recovery was significantly longer for neutrophils than for leukocytes. In the clinical setting, the parameter "leukocyte count" has been occasionally used for evaluation of the severity of myelosuppression, because the data is more readily available. However, at least during the nadir, the "neutrophil count" should be used as the parameter of choice.

Antineoplastic Agents↗
PubMed2000

Theophylline induces neutrophil apoptosis through adenosine A2A receptor antagonism.

This study was designed to determine whether theophylline would augment granulocyte apoptosis via a mechanism of adenosine A2A receptor antagonism. A selective adenosine A2 receptor agonist (CGS-21680, 1 microM) exhibited the most efficient potency for decreasing neutrophil apoptosis for 16 h from 63+/-5 to 19+/-4% (P < 0.001); it exerted poor and adverse effects on eosinophil survival. A selective protein kinase A inhibitor KT-5720 (10 microM) reversed the capacity of dibutyryl cAMP but not CGS-21680 to induce an inhibitory effect on neutrophil apoptosis, suggesting that occupancy of adenosine A2 receptors inhibit neutrophil apoptosis by a cAMP-independent mechanism. Theophylline derivatives show the following pattern of potency for inducing neutrophil apoptosis competing with CGS-21680: 8-phenyltheophylline = 8-p-sulfophenyltheophylline > theophylline >> enprofylline. This pattern is consistent with the affinity established for A2A receptors. Theophylline demonstrated an additive effect to that of anti-Fas antibody (CH11, 1 microg/mL) in inducing neutrophil apoptosis, but not to that of adenosine deaminase or KF-17837 (a selective A2 receptor antagonist; 1 microM), suggesting conflicting effects on the receptor antagonism. These findings suggest that theophylline has an immunomodulatory action on neutrophil apoptosis via a mechanism of A2A antagonism.

Adenosine↗
PubMed2000

Induction of protein kinase Czeta-related protein kinase by growth suppression in carcinogen-initiated epidermal cell-line WYF31 cells.

In primary cultured mouse epidermal cells, protein kinase C isozyme zeta (PKCzeta) consists of multiple forms, for example, low-salt eluted PKCzeta (1-PKCzeta; 79 and 85 kDa) and high-salt eluted PKCzeta (h-PKCzeta; 79 and 85 kDa) on anion-exchange column chromatography. In this study, biochemical and biophysical differences between 1-PKCzeta and h-PKCzeta were examined by using carcinogen-initiated mouse epidermal cell-line WYF31 cells, whose growth is stimulated by tumour promoter phorbol 12-myristate 13-acetate (PMA). The binding efficiency of h-PKCzeta to anti-PKCzeta antibody-affinity column was 10 times higher than that of 1-PKCzeta. T7-tagged rat PKCzeta overexpressed in WYF31 cells was recovered only in the high-salt eluted area on the anion-exchange column. Furthermore, when rat PKCzeta was stably overexpressed in WYF31 cells, the content of h-PKCzeta increased 4 to 5 times compared to that of parental cells, but the content of 1-PKCzeta was not altered. All of these results indicate that h-PKCzeta is the product of the PKCzeta gene (referred to as PKCzeta) and that 1-PKCzeta is closely related but different from PKCzeta (referred to as PKCzeta-related kinase). Interestingly, serum starvation of WYF31 cells caused a marked increase of the content of PKCzeta-related kinase with a concomitant decrease of PKCzeta content. These changes were reversed by stimulating the cell growth with 10% foetal calf serum. Prolonged treatment of starved cells with PMA, which induces the proliferation of WYF31 cells, also caused the downregulation of PKCzeta-related kinase. These results suggest that the expression levels of PKCzeta-related kinase and PKCzeta are differently regulated, and that the increased expression of PKCzeta-related kinase might play a significant role in the growth-suppression processes of WYF31 cells.

Amino Acid Sequence↗
PubMed2000

Relationship between the morphological and biological characteristics of intraductal components accompanying invasive ductal breast carcinoma and patient age.

We divided 324 cases with invasive ductal breast carcinoma into three age groups, and investigated the differences in proliferative activity and extension of the intraductal components among the age cohorts. Proliferative activity was expressed as the number of MIB1-positive nuclei per 1000 cancer cells in the intraductal components (MLI), and the intraductal component extension farthest from the invasive focus was defined as the maximum distance of ductal spread (MXDS). Moreover, analyses were conducted for three grade types, classified according to the classification system of ductal carcinoma in situ. The under-40 age group had significantly higher MXDS values than the other two age groups (p = 0.0280), and this trend was more marked in those with the non-high grade without necrosis type (p = 0.0045). The under-40 age group had higher MLIs, but the differences did not reach statistical significance (p = 0.0793). In regard to those with the high grade type, the under-40 age group had significantly higher MLIs than the other two age groups (p = 0.0269), and this trend was not significant in the cases with any other grade types. Associations between the age group and the margin status of the lumpectomy specimens were investigated in the 143 cases in which breast conserving surgery was tried. The under-40s had a significantly higher margin-positive rate in their lumpectomy specimens than the other two age groups (= 0.0362), and this trend was also seen in the groups with the non-high grade without necrosis type (p = 0.0256). These results confirm the importance of considering patient age when designing surgical procedures for breast conserving therapy.

Adult↗
PubMed2000

Rho kinase inhibitor HA-1077 prevents Rho-mediated myosin phosphatase inhibition in smooth muscle cells.

In smooth muscle, a Rho-regulated system of myosin phosphatase exists; however, it has yet to be established whether Rho kinase, one of the downstream effectors of Rho, mediates the regulation of myosin phosphatase activity in vivo. In the present study, we demonstrate in permeabilized vascular smooth muscle cells (SMCs) that the vasodilator 1-(5-isoquinolinesulfonyl)-homopiperazine (HA-1077), which we show to be a potent inhibitor of Rho kinase, dose dependently inhibits Rho-mediated enhancement of Ca(2+)-induced 20-kDa myosin light chain (MLC(20)) phosphorylation due to abrogating Rho-mediated inhibition of MLC(20) dephosphorylation. By an immune complex phosphatase assay, we found that guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS) stimulation of permeabilized SMCs caused a decrease in myosin phosphatase activity with an increase in the extent of phosphorylation of the 130-kDa myosin-binding regulatory subunit (MBS) of myosin phosphatase in a Rho-dependent manner. HA-1077 abolished both of the Rho-mediated events. Moreover, we observed that the pleckstrin homology/cystein-rich domain protein of Rho kinase, a dominant negative inhibitor of Rho kinase, inhibited GTPgammaS-induced phosphorylation of MBS. These results provide direct in vivo evidence that Rho kinase mediates inhibition of myosin phosphatase activity with resultant enhancement of MLC(20) phosphorylation in smooth muscle and reveal the usefulness of HA-1077 as a Rho kinase inhibitor.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2000

Effects of theophylline on human eosinophil functions: comparative study with neutrophil functions.

The understanding of theophylline as a bronchodilator has been reconsidered in recent years. We undertook to determine its immunomodulatory actions in granulocytes and elucidate their mechanism. Preincubation of neutrophils with theophylline (10(-5) to 5 x 10(-3) M) had a biphasic effect on O2(-) production stimulated with N-formyl-methionyl-leucyl-phenylalanine or C5a. Theophylline potentiates O2(-) production via adenosine A(2A) receptor antagonism induced by receptor-linked agonists from neutrophils, but not from eosinophils. The addition of theophylline caused a significant decline in neutrophil chemotaxis at lower concentrations than those for eosinophil motility. Theophylline reduces neutrophil chemotaxis via adenosine A1 receptor antagonism. At high concentrations, with an intracellular cAMP accumulation as a result of phosphodiesterase (PDE) inhibition, theophylline also exerts an inhibitory effect on the O2(-) production and chemotaxis of both types of cells. The difference in theophylline's effect on neutrophils and eosinophils appears to depend on the existence of specific adenosine receptors. Theophylline thus modulates granulocyte functions in association with specific adenosine receptor antagonism and cAMP-PDE inhibition.

Bronchodilator Agents↗
PubMed1999

Maximum Density of Tumor Staining Obtained by Preoperative IV-DSA as a Prognostic Indicator for Node-Negative Breast Cancer.

BACKGROUND: We previously demonstrated that the density of tumor enhancement by intravenous digital subtraction angiography (IV-DSA) is correlated with the number of tumor microvessels and that the incidence of distant metastasis is highin patients with breast cancer who show a high maximum density of tumor enhancement (MAX) on IV-DSA. In the present study, we evaluated the prognostic value ofMAX for node-negative breast cancer patients. Patients and METHODS: A total of 128 node-negative breast cancer patients underwent preoperative IV-DSA, and the region of interest (ROI) was set in the areas enhanced by IV-DSA of the breast. MAX was calculated by the time-density curve. Patients were divided into two subgroups: those with MAX >/= 9 (n=35) and those with MAX < 9 (n=93). RESULTS: Patients with recurrence had a significantly higher MAX value than those without recurrence (11.8 +/- 3.8 vs 7.1 +/- 3.0, p<0.01). The disease-free survival rate was significantly worse in patients with higher MAX values than in those with lower MAX values (p <0.001). Multivariate analysis showed that MAX was the strongest predictor of disease-free survival (p =0.026). CONCLUSIONS: These results suggest that the maximum density obtained by IV-DSA is a strong, independent prognostic indicator for node-negative breast cancer patients.

Journal Article↗
PubMed1999

Plasma cell generation from B-lymphocytes via CD27/CD70 interaction.

To produce antibodies, the differentiation of B cells into antibody-secreting cells, plasma cells, is required. We describe that ligation of CD27, which belongs to the tumor necrosis factor receptor (TNFR) family and is a memory marker of B cells, yields crucial signals that positively control the entry of B cells into the pathway to plasma cells. The triggering via CD27 by CD27 ligand (CD70) on purified peripheral blood B cells yielded an increase in the number of plasma cells in the presence of interleukin-10 (IL-10). The differentiation into plasma cells by a combination of IL-10 and CD70-transfectants occurred in CD27+ B cells, but not in CD27- B cells. Moreover, the addition of IL-2 to the IL-10 and CD70-transfectants greatly induced the differentiation into plasma cells. In the presence of only IL-2, IL-4 or IL-6, CD70-transfectants did not promote the differentiation into plasma cells. On the other hand, CD40 signaling increased the expansion of a B cell pool from peripheral blood B cells primarily activated by IL-2, IL-10 and anti-CD40 mAb. These data demonstrate that CD27 ligand (CD70) is a key molecule to direct the differentiation of CD27+ memory B cells toward plasma cells in cooperation with IL-10.

Animals↗
PubMed1998

CD27/CD70 interaction augments IgE secretion by promoting the differentiation of memory B cells into plasma cells.

The induction of IgE switching in B cells requires several signals given by cytokines and cell contact-delivered signals. Here, we investigated the role of CD27/CD70 interaction in B cell IgE synthesis. The addition of CD27 ligand (CD70) transfectants to B cell cultures increased the IgE synthesis synergistically in the presence of IL-4 plus anti-CD40 mAb (anti-CD40). The effect of CD70 transfectants was dose dependent and was completely blocked by anti-CD70 mAb. CD27+ B cells had the ability to produce IgE, which was increased by contact with CD70 transfectants, whereas CD27- B cells did not produce IgE. CD27/CD70 interaction enhanced B cell proliferation in the presence of IL-4 or IL-4 plus anti-CD40. The augmentation of B cell proliferation by CD70 transfectants was apparent in CD27+ B cells, but was mild in CD27- B cells. The helper activity for IgE synthesis by the CD27/CD70 interaction did not contribute to the enhancement of germline epsilon transcripts. Flow cytometric and morphological analyses demonstrated that the addition of CD70 transfectants to B cell cultures remarkably promoted differentiation into plasma cells in the presence of IL-4 and CD40 signaling. Finally, CD27 cross-linking resulted in the up-regulation of positive regulatory domain I-binding factor-1. Taken together, our findings indicate that signaling via CD27 on B cells induces IgE synthesis, in cooperation with IL-4 and CD40 signaling, by promoting the generation of plasma cells through up-regulation of positive regulatory domain I-binding factor-1.

Adult↗
PubMed1998

HA1077, a protein kinase inhibitor, inhibits calponin phosphorylation on Ser175 in porcine coronary artery.

Calponin is a thin filament-associated protein which has been implicated in the modulation of the contractile state of smooth muscle via its interaction with actin and inhibition of the actin-activated myosin Mg-ATPase. This inhibitory effect is alleviated by phosphorylation of calponin at Ser175 in vitro by protein kinase C. The issue of calponin phosphorylation in intact smooth muscle in response to agonists that activate protein kinase C is controversial. We have produced a monoclonal antibody that specifically recognizes calponin phosphorylated at Ser175 and used it to analyze calponin phosphorylation in porcine coronary arterial smooth muscle stimulated with prostaglandin F2alpha or phorbol 12,13-dibutylate (PDB). Calponin phosphorylation increased rapidly in response to prostaglandin F2alpha concomitant with the increase in tension. Calponin was then dephosphorylated while force was maintained. Tension development in response to PDB was significantly slower, but again calponin phosphorylation paralleled force development. In this case, calponin dephosphorylation was very slow, consistent with prolonged activation of protein kinase C. The protein kinase inhibitors, HA1077 (1-5-(isoquinoline sulfonyl)-homopiperazine HCl) and HA1100 (1-hydroxy HA1077; 1-(hydroxy-5-isoquinoline sulfonyl-homopiperazine), inhibited tension development and calponin phosphorylation in a concentration-dependent manner with similar ED50 values in response to prostaglandin F2alpha and PDB. These results support physiological roles for calponin in force development in smooth muscle in response to agonists which trigger protein kinase C activation and in the latch state, i.e., force maintenance at low energy cost. Furthermore, the vasodilator effect of HA1077 and HA1100 is more likely due to inhibition of protein kinase C than of myosin light chain kinase.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1998

Absence of IgD-CD27(+) memory B cell population in X-linked hyper-IgM syndrome.

The present study analyzed peripheral blood B cell populations separated by IgD and CD27 expression in six males with X-linked hyper-IgM syndrome (XHIM). Costimulation of mononuclear cells from most of the patients induced no to low levels of class switching from IgM to IgG and IgA with Staphylococcus aureus Cowan strain (SAC) plus IL-2 or anti-CD40 mAb (anti-CD40) plus IL-10. Measurable levels of IgE were secreted in some of the patients after stimulation with anti-CD40 plus IL-4. Costimulation with SAC plus IL-2 plus anti-CD40 plus IL-10 yielded secretion of significant levels of IgG in addition to IgM, but not IgA. The most striking finding was that peripheral blood B cells from all of the six patients were composed of only IgD+ CD27(-) and IgD+ CD27(+) B cells; IgD- CD27(+) memory B cells were greatly decreased. IgD+ CD27(+) B cells from an XHIM patient produced IgM predominantly. Our data indicate that the low response of IgG production in XHIM patients is due to reduced numbers of IgD- CD27(+) memory B cells. However, the IgG production can be induced by stimulation of immunoglobulin receptors and CD40 in cooperation with such cytokines as IL-2 and IL-10 in vitro.

Adolescent↗
PubMed1998

Acinic Cell Adenocarcinoma Arising in the Breast of a Young Male: A Clinicopathological, Immunohistochemical and Ultrastructural Study.

A 23-year-old man with acinic cell adenocarcinoma of the breast is reported. He presented with a 4.8 x 4.2 cm mass in his left breast, and excisional biopsy was performed. Under the light microscope, tumor cells had abundant periodic acid-Schiff-positive secretory granules and eosinophlic cytoplasms. Electron microscopy revealed the granules to have various electron densities, a finding characteristic of acinic cell adenocarcinoma. Immunohistochemically, the tumor cells were stained with salivary-type amylase. Electron microscpic and immunohistochemical investigation greatly facilitated the diagnosis of this acinic cell adenocarcinoma, which was in an unusual location. We believe this is the first case report of acinic cell adenocarcinoma of the mammary gland studied utilizing light microscopic, ultrastructural and immunohistochemical techniques.

Journal Article↗
PubMed1998

Generation of plasma cells from peripheral blood memory B cells: synergistic effect of interleukin-10 and CD27/CD70 interaction.

B cells can differentiate into the antibody-secreting cells, plasma cells, whereas the crucial signals that positively control the entry into the pathway to plasma cells have been unclear. Triggering via CD27 by CD27 ligand (CD70) on purified peripheral blood B cells yielded an increase in the number of plasma cells in the presence of interleukin-10 (IL-10). Differentiation into plasma cells by a combination of IL-10 and CD70 transfectants occurred in CD27+ B cells but not in CD27- B cells. Moreover, addition of IL-2 to the IL-10 and CD70-transfect activation system greatly induced differentiation into plasma cells. In the presence of only IL-2, IL-4, or IL-6, CD70 transfectants did not promote differentiation into plasma cells. On the other hand, CD40 signaling increased the expansion of a B-cell pool from peripheral blood B cells primarily activated by IL-2, IL-10, and anti-CD40 monoclonal antibody (MoAb). Finally, CD27 signaling also rescued B cells from IL-10-mediated apoptosis. These data demonstrate that CD27 ligand (CD70) is a key molecule to prevent the IL-10-mediated promotion of apoptosis and to direct the differentiation of CD27+ memory B cells toward plasma cells in cooperation with IL-10.

Adult↗