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Biomedical subjects

N Watanabe

Publications and source records attributed to N Watanabe.

At least 343 records · Page 19Linked to original sources
PubMed1998

Interleukin-10 reduces natural killer sensitivity and downregulates MHC class I expression on H-ras-transformed cells.

We examined the effect of IL-10 on sensitivity to NK-cell-mediated cytotoxicity of the H-ras-induced transformants, W14 and W31. Incubation of cells with recombinant human (rh) IL-10 resulted in a dose-dependent decrease in the expression of MHC class I antigens, but not in the ICAM-1 expression. However, prior incubation of W31 cells with rhIL-10 markedly decreased their susceptibility to cytolysis by rat splenic NK cells. This fact suggested that the IL-10-mediated decrease in MHC class I expression might not dominate the regulation of the NK sensitivity. This was true when rat IL-10 cDNA-introduced W31 cells were used as an endogenous IL-10 producer. The NK sensitivity in vitro of W31T-H, a high IL-10-producer clone, was suppressed downward to the equivalent level of W31 cells pretreated with exogenous rhIL-10. The decreased NK-sensitivity of W31T-H cells was further confirmed by in vivo Winn assay, in which nude mice challenged with W31T-H cells and rat NK cells together developed tumors, whereas nude mice challenged with W31T-L, a minimal-IL-10 producer clone, and NK cells did not. Since neither exogenous nor endogenous IL-10 affected the proliferation of W31 cells, the data indicated that W31T-H cells could evade the NK-cell-mediated immune response in vivo. Taken together, our data reveal a novel mechanism for an IL-10-mediated escape of tumor cells from host immune system by NK cells.

Animals↗
PubMed1998

CD45RChighCD4+ intestinal mucosal lymphocytes infiltrating in the inflamed colonic mucosa of a novel rat colitis model induced by TNB immunization.

To clarify the role of CD4(+) intestinal mucosal lymphocytes in chronic intestinal inflammation, we developed a new rat colitis model by immunization with 2,4,6-trinitrobenzenesulfonic acid (TNB) in an emulsion with an adjuvant followed by transrectal administration of a low dose of TNB. Moreover, we assessed the therapeutic effect of anti-CD4 monoclonal antibody (mAb) on this model. In concert with the development ofserum anti-TNB Abs, transmural and segmental colitis that mimics some characteristics of human Crohn's disease was induced in the immunized rats. Immunohistochemical analysis showed the increase of infiltrating lamina propria CD4(+) T cells. Flow-cytometric analysis of isolated cells from inflamed mucosa revealed that CD45RChighCD4(+) T cells were significantly increased. Interestingly, intraperitoneal administration of anti-CD4 mAbs could suppress severe inflammation in the model with decrease of anti-TNB Ab titer. After the treatment with anti-CD4 mAbs, CD45RChighCD4(+) T cells in the lamina propria and interferon-gamma mRNA expression in the colonic lamina propria CD4(+) T cells were decreased. These results indicated that Th1 CD4(+) intestinal mucosal T cells have a role in the progress of inflamed lesions in chronic enteritis. They implicate that a therapy targeting mucosal T cells expressing CD4 may be feasible in the treatment of human Crohn's disease.

Animals↗
PubMed1998

Activation of interleukin-1beta-converting enzyme by nigericin is independent of apoptosis.

Interleukin-1beta-converting enzyme (ICE) is believed to be one of the key proteases involved in apoptosis. Since the precursor form of interleukin-1beta (pre-IL-1beta) is one of the well known substrates for ICE, and a potassium/proton ionophore, nigericin, enhances IL-1beta processing, the authors hypothesized that nigericin induces apoptosis through the activation of ICE. In a lipopolysaccharide (LPS)-stimulated and nigericin-treated human monocytic cell line, THP-1, apoptosis was induced, as assessed as to a decrease in cell size, chromatin condensation, exposure of phosphatidylserine and DNA fragmentation. Under exactly the same conditions, nigericin also induced IL-1beta processing in these cells, which was significantly inhibited by an ICE inhibitor, acetyl-Tyr-Val-Ala-Asp-CHO. On the contrary, treatment with this inhibitor at the same concentration did not inhibit nigericin-induced apoptosis, assessed as to the decrease in cell size, chromatin condensation and DNA fragmentation. Although apoptosis induced by nigericin was also observed for LPS-stimulated human peripheral blood mononuclear cells and a mouse T lymphoma cell line, EL-4, the ICE inhibitor did not inhibit the apoptosis in the cells. These results suggest that activated ICE is not involved in the apoptosis induced by nigericin. Since apopain activity was not augmented under the same conditions, neither ICE nor apopain may play any role in the nigericin-induced apoptosis.

Animals↗
PubMed1998

Prevention of small intestinal ischemia-reperfusion injury in rat by anti-cytokine-induced neutrophil chemoattractant monoclonal antibody.

The function of cytokine-induced neutrophil chemoattractant (CINC), which is the rat counterpart to human growth-related gene product belonging to the CXC chemokine subgroup, is based principally on neutrophil-specific chemotactic activity. In addition, we previously reported that plasma CINC was elevated during the period of small intestinal ischemia-reperfusion injury, and that there was a correlation between the degree of mucosal damage and the peak level of CINC after reperfusion, suggesting that CINC may play a major role in neutrophil infiltration into the rat small intestinal ischemia-reperfusion injury site. Thus, we investigated whether administration of anti-CINC monoclonal antibodies (mAbs) reduces small intestinal ischemia-reperfusion injury. Small intestine was subjected to ischemia for 3 h by occlusion of the anterior mesenteric artery with an atraumatic vascular clump. After infusion of anti-CINC mAbs or isotype-matched mAbs, the intestine was subjected to reperfusion. The pretreatment with anti-CINC mAbs attenuated ischemia-reperfusion injury in the small intestine, in association with the reduction of tumor necrosis factor-alpha and myeloperoxidase production, and resulted in the prolongation of survival. It is concluded that CINC plays an important role in the onset of rat small intestinal ischemia-reperfusion injury. In addition, blocking the action of CINC, namely, the neutrophil chemotactic activity, may be useful in preventing ischemia-reperfusion injury in the small intestine.

Animals↗
PubMed1998

[Surgical stabilization of multiple rib fractures successfully achieved with the use of long metalic plates].

Surgical stabilization of multiple rib fractures in 5 male patients was successfully achieved with the use of orthopedic A-O metalic plates, which are called reconstruction plates. In each patient, we prevented deformity of the rib cage and flail chest which frequently occurs after multiple rib fractures. Three of these patients received emergency operations because of severe hemopneumothorax and flail chest due to crushing injuries to the chest. They were treated by the standard thoracotomy, hemostasis of intrapleural bleeding, and stabilization of fractured ribs with reconstruction plates, in addition two of the patients underwent a single lobectomy to control the pulmonary hemorrhage. Another two patients were treated with mechanical ventilation and closed-tube thoracotomy following the chest trauma because their thoracic bleeding from drainage tubes was tolerable. But flail chest and respiratory insufficiency did not improve, in spite of positive controlled ventilation as a mode of internal pneumatic stabilization. Then surgical stabilization of the fractured ribs with these plates was carried out ten to twelve days after the accidents in each case. All patients tolerated the surgical procedures well and were successfully removed from the respirator, demonstrating complete stability of the chest wall. The long metal reconstruction plates with many perforations were very useful for the external fixation of segmentary fractured ribs as an external brace. This was because they were long enough to cover the whole length of the fractured ribs and moderately soft enough to be appropriately bent or twisted by hand at the time of operation. Moreover a number of holes in it allowed the suture to pass through the plate and rib, avoiding displacement of the prosthesis. This is the first report which describes the usefulness of orthopedic reconstruction plates for the stabilization of multiple rib fractures.

Adult↗
PubMed1998

Diffusion-weighted echo-planar MRI of lacunar infarcts.

We studied 35 patients with lacunar infarcts, using diffusion-weighted echo-planar imaging (DW-EPI) at 1.5 T. The relative apparent diffusion coefficient ratio (ADCR) of each lesion was calculated and lesion conspicuity on DW-EPI was compared to that on images acquired with fast fluid-attenuated inversion recovery and T2-weighted fast spin-echo sequences. Acute small infarcts (within 3 days) were identified with DW-EPI as an area of decreased ADCR (range 0.33-0.87; mean 0.67) and high signal, subacute small infarcts (4-30 days) as a high-signal or isointense areas of decreased or nearly normal ADCR (0.54-0.98; 0.73), and chronic small infarcts (> 30 days) as low- or high-signal areas of nearly normal or increased ADCR (0.97-1.92; 1.32). In three patients, small infarcts of the brain stem in the hyperacute phase (within 6 h) were seen only with DW-EPI. In five patients, fresh small infarcts adjacent to multiple old infarcts could be distinguished only with DW-EPI.

Aged↗
PubMed1998

Antibody-dependent difference in biodistribution of monoclonal antibodies in animal models and humans.

The study was designed to clarify the difference in pharmacokinetics of monoclonal antibodies (mAb) in animal models and humans, and to elucidate the applicability of animal models. 99mTc-labeled murine mAb -- against carcinoembryonic antigen (designated BW431/26), and neural cell adhesion molecule (NE150) -- and one chimeric mouse/human mAb against nonspecific cross-reacting antigen (chNCA) were administered i.v. to normal mice and athymic mice (370 kBq, 400 ng) xenografted with human cancer cells expressing antigens, and into patients with tumor (925 MBq, 1 mg). The biodistribution of two of the three mAb (not 99mTc-BW431/26) differed clearly in mice and patients. 99mTc-NE150 showed specific uptake in xenografted tumor and otherwise a normal biodistribution; however, clinical examination showed increased uptake in the liver with rapid blood clearance (mean alpha half-life = 31.1 min) compared with 99mTc-BW431/26 (28.4 h). 99mTc-chNCA demonstrated increased blood clearance and renal excretion in both normal and athymic mice, with accumulation in tumors. Clinical examination showed rapid blood clearance (mean alpha half-life = 6.4 min) and increased uptake in the liver. High-performance liquid chromatographic analysis of 99mTc-chNCA revealed the immune complex in blood, suggesting uptake of the complex by the reticuloendothelial cells. The biodistribution of radiolabeled mAb in animal and human models was variable and specific for each of the three mAb. The results of animal studies with mAb should be evaluated carefully before being extrapolated to humans, on the basis of the nature of the mAb and interacting substances.

Animals↗
PubMed1998

Downregulation of cytokine-induced neutrophil chemoattractant and prolongation of rat liver allograft survival by interleukin-10.

We investigated whether the administration of recombinant human interleukin-10 (rhIL-10) regulates the production of cytokine-induced neutrophil chemoattractant (CINC) and improves graft survival in rat orthotopic liver transplantation (OLTx). Allograft recipients received injections of rhIL-10 at doses of 2, 10, 20, or 50 micrograms/kg/day. The allograft recipients that received rhIL-10 at 10 or 20 micrograms/kg/day showed a slight but significant prolongation of graft survival to 13.0 +/- 0.4 and 13.8 +/- 0.3 days, respectively, compared with 9.6 +/- 0.2 days in untreated allografts. Conversely, the administration of high-dose rhIL-10 shortened the allograft survival. In the rhIL-10 treatment groups, the mean serum and tissue levels of CINC at every time point after OLTx were reduced significantly compared with those in the no-treatment group. The mean peak neutrophil counts in the peripheral circulation (PC) of the groups given rhIL-10 at 10, 20, or 50 micrograms/kg/day from the samples obtained 12h after reperfusion were decreased significantly compared with the no-treatment group. Furthermore, the mean peak neutrophil counts in the PC of the groups given rhIL-10 at 10 or 20 micrograms/kg/day from the samples obtained between postoperative days (PODs) 7 and 10 were decreased significantly compared with the no-treatment group. The magnitude of liver damage and leukocyte infiltration in the rhIL-10-treated allografts on PODs 1 and 7 was reduced compared with that of untreated allografts. Our data indicate that the administration of rhIL-10 downregulates CINC production during the period of reperfusion injury and acute cellular rejection after OLTx, and prolongs liver allograft survival, suggesting that IL-10 therapy is potentially beneficial in OLTx.

Animals↗
PubMed1998

Molecular discrimination of enterotoxin C subtype in clinical isolates of Staphylococcus aureus.

The subtype of staphylococcal enterotoxin C (SEC) of 33 S. aureus clinical isolates was determined by polymerase chain reaction and direct DNA sequencing of a portion of the SEC gene encoding the SEC subtype-specific region. With the exception of a single strain with the SEC2 gene, all other strains showing different biologic and genetic properties were proved to possess the SEC3 gene.

DNA Primers↗
PubMed1998

PKA and MPF-activated polo-like kinase regulate anaphase-promoting complex activity and mitosis progression.

Ubiquitin-mediated proteolysis is the key to cell cycle control. Anaphase-promoting complex/cyclosome (APC) is a ubiquitin ligase that targets cyclin B and factors regulating sister chromatid separation for proteolysis by the proteasome and, consequently, regulates metaphase-anaphase transition and exit from mitosis. Here we report that Cdc2-cyclin B-activated Polo-like kinase (Plk) specifically phosphorylates at least three components of APC and activates APC to ubiquitinate cyclin B in the in vitro-reconstituted system. Conversely, protein kinase A (PKA) phosphorylates two subunits of APC but suppresses APC activity. PKA is superior to Plk in its regulation of APC, and Plk activity peaks whereas PKA activity is falling at metaphase. These results indicate that Plk and PKA regulate mitosis progression by controlling APC activity.

3T3 Cells↗
PubMed1998

Electroencephalogram abnormality and high-dose busulfan in conditioning regimens for stem cell transplantation.

High-dose busulfan (BU) is widely used in combined chemotherapy before allogeneic or autologous bone marrow transplantation. Convulsions are reported as a side-effect of high-dose BU. We recorded electroencephalograms (EEGs) before and on the third day of BU administration in 22 patients. Abnormal EEGs were observed on the third day in 13 cases (59%). These patients were older (P < 0.05) and had had larger doses of BU (P < 0.025) than the nine patients with normal EEGs. Convulsions occurred in two of the 22 patients, one of whom was receiving prophylaxis with phenytoin. Gamma aminobutyric acid (GABA), a natural mediator of defense against epileptic activity, concentrations in cerebrospinal fluid measured before and after administration of BU showed no definite changes.

Adolescent↗
PubMed1998

Eosinophilia, IgE production, and cytokine production by lung T cells in surface CD4-deficient mutant mice infected with Toxocara canis.

Mutant mice deficient in CD4+ T cells and their normal and heterozygous littermates were infected with Toxocara canis, and compared for eosinophilia, total and Toxocara-specific immunoglobulin E (IgE) production, and in vitro cytokine production by lung cells. The numbers of eosinophils in the peripheral blood of normal and heterozygous mice peaked on days 10 and 21, although mutant mice showed eosinophilia with a peak on day 10. This indicates that the first peak on day 10 is CD4 independent and the second peak is CD4 dependent. Before infection, the levels of total IgE had no significant difference among the three groups of mice. Total and Toxocara-specific IgE in all genotypes of mice increased after infection, and was the highest in normal mice and the lowest in mutant mice. In vitro production of interleukin (IL)-5 and IL-4 by total lung cells was the highest in normal mice and the lowest in mutant mice. CD4+ and CD4- CD8- T lymphocytes, but not CD8+ T lymphocytes produced IL-5 and IL-4 when incubated with anti-CD3 monoclonal antibody (mAb) and lung-adherent cells. These results indicated that IL-5 and IL-4 were produced mainly by CD4+ cells and partly by CD4- CD8- cells, but not by CD8+ cells. In addition, cytokine production by CD4+ cells was affected by the number of CD4 molecules on their surface.

Animals↗
PubMed1998

Antigen receptor cross-linking by anti-immunoglobulin antibodies coupled to cell surface membrane induces rapid apoptosis of normal spleen B cells.

Cross-linking of surface immunoglobulin (sIg) has been shown to induce either activation or apoptosis of mature B cells presumably depending on the nature of antigens. However, the nature of antigens for induction of mature B-cell apoptosis is not yet fully understood. We cross-linked sIg of mature B cells with various amounts of either anti-Ig antibodies in the soluble form or anti-Ig coupled to erythrocytes or myeloma cells as surrogate membrane-bound antigens. Anti-Ig antibodies coupled to cell surface membrane induced rapid and extensive apoptosis of normal spleen B cells even in the absence of signalling via the Fc receptor. In contrast, soluble anti-Ig induced proliferation or apoptosis of mature B cells depending on the concentration of anti-Ig. The extent of apoptosis induced by soluble anti-Ig was limited compared to that induced by membrane-bound anti-Ig. These results suggest that mature B cells undergo apoptosis or proliferation depending on whether antigens are soluble or membrane-bound and on antigen doses.

Animals↗
PubMed1998

Differential expression of multidrug resistance (mdr) and canalicular multispecific organic anion transporter (cMOAT) genes following extrahepatic biliary obstruction in rats.

The hepatic canalicular membrane has transporters that play an important role as efflux pumps in the excretion of endogenous bile constituents or xenobiotics into bile canaliculi. To elucidate functional significance of canalicular transporters in the mechanism of cholestasis, mRNA expression levels of multidrug resistance (mdr) 1b, mdr2 and canalicular multispecific organic anion transporter (cMOAT) genes were analyzed by Southern blotting of reverse-transcribed PCR products of liver mRNA obtained from cholestatic rats that had been subjected to bile duct ligation. Both mdr1b and mdr2 mRNA expression increased after ligation. Immunohistochemical study revealed that the products of both mdr1b and mdr2 were present on the canaliculi, and that their levels increased after ligation. In contrast, cMOAT mRNA expression was not increased, but rather attenuated by ligation. The expression of canalicular transporters was differentially regulated in extrahepatic biliary obstruction, indicating the different roles are played by mdr and cMOAT in the pathogenesis of cholestasis.

ATP Binding Cassette Transporter, Subfamily B↗