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Biomedical subjects

F Nagase

Publications and source records attributed to F Nagase.

At least 19 recordsLinked to original sources
PubMed2001

Superoxide-mediated early oxidation and activation of ASK1 are important for initiating methylglyoxal-induced apoptosis process.

Methylglyoxal (MG) is a physiological metabolite, but it is known to be toxic, inducing stress and causing apoptosis. Our previous studies demonstrated that MG induced apoptosis in Jurkat cells by activating the c-Jun N-terminal kinase (JNK) signal transduction pathway, which induced an obvious decrease in mitochondrial membrane potential, followed by caspase-3 activation. Here, we observed that MG-induced apoptosis was associated with both rapid production of superoxide anion (O(2)(-)) followed by a marked increase in ROS and striking and temporal activation of ASK1. Overexpression of wild-type ASK1 could enhance the rate of apoptosis induced by MG, whereas the expression of the kinase-inactive form of ASK1 notably prevented cells from MG-induced death. NAC and PDTC blocked the activation of ASK1 and MG-induced apoptosis completely. Moreover, nonthiol antioxidants SOD-mimic MnTBAP and catalase together obviously inhibited MG-induced ASK1 activation and apoptosis induction. Correspondingly, MG-mediated ASK1 activation was enhanced by diethyldithiocarbamate (DDC). Addition of antioxidant into the culture of cells at a later stage (4-8 h after the initial MG treatment) failed to prevent their death. These results suggest that activating ASK1 at the early stage linking to production of O(2)(-) is crucial for subsequent progression of apoptosis in MG-treated Jurkat cells.

Acetylcysteine↗
PubMed2000

Mercuric chloride stimulates distinct signal transduction pathway for DNA synthesis in a T-cell line, CTLL-2.

Exposure of an interleukin-2 (IL-2)-dependent murine T-cell line (CTLL-2) to mercuric chloride in in vitro culture induced a low but definite level of DNA synthesis in the absence of exogenous IL-2, and further enhanced the IL-2-induced DNA synthesis. Addition of anti-IL-2 or anti-IL-4 antibody to the culture, which neutralized all of the IL-2 or IL-4 activity, respectively, never inhibited the mercuric chloride-mediated DNA synthesis. Correspondingly, no detectable level of IL-2, IL-4, and IL-15 mRNA was found in mercuric chloride-treated CTLL-2 cells in our test condition. Stimulation of CTLL-2 cells with IL-2 induced phosphorylation on extracellular signal-regulated kinases more intensively than on c-Jun NH2-terminal kinases (JNKs), and provoked tyrosine phosphorylation of Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). In contrast, by mercuric chloride stimulation, JNKs and c-Jun were preferentially phosphorylated, but no detectable level of phosphorylation was induced on JAKs and STATs. These findings provided a possibility that mercuric chloride promoted lymphocyte proliferation through a JNK-linked signal cascade in CTLL-2 cells, which differs from that triggered by IL-2.

Animals↗
PubMed2000

Methylglyoxal induces apoptosis in Jurkat leukemia T cells by activating c-Jun N-terminal kinase.

Methylglyoxal (MG) is a physiological metabolite, but it is known to be toxic, inducing stress in cells and causing apoptosis. This study examines molecular mechanisms in the MG-induced signal transduction leading to apoptosis, focusing particularly on the role of JNK activation. We first confirmed that MG caused apoptosis in Jurkat cells and that it was cell type dependent because it failed to induce apoptosis in MOLT-4, HeLa, or COS-7 cells. A caspase inhibitor, Z-DEVD-fmk, completely blocked MG-induced poly(ADP-ribose)polymerase (PARP) cleavage and apoptosis, showing the critical role of caspase activation. Inhibition of JNK activity by a JNK inhibitor, curcumin, remarkably reduced MG-induced caspase-3 activation, PARP cleavage, and apoptosis. Stable expression of the dominant negative mutant of JNK also protected cells against apoptosis notably, although not completely. Correspondingly, loss of the mitochondrial membrane potential induced by MG was decreased by the dominant negative JNK. These results confirmed a crucial role of JNK working upstream of caspases, as well as an involvement of JNK in affecting the mitochondrial membrane potential.

Animals↗
PubMed2000

Midgut malrotation in adulthood.

A 29-year-old man was admitted to our hospital with a history of recurrent right upper quadrant abdominal pain and vomiting. These symptoms appeared intermittently for 7 years. Various examinations revealed a diagnosis of midgut malrotation. Laparotomy was performed and revealed reverse rotation of the duodenum with paraduodenal hernia and a normal rotating colon. This case suggests that recurrent abdominal complaints in an adult should arouse suspicion of midgut malrotation.

Abdominal Pain↗
PubMed1998

Induction of apoptosis and tyrosine phosphorylation of cellular proteins in T cells and non-T cells by stimulation with concanavalin A.

A high concentration (30 microg/ml or more) of Con A caused the death of not only thymocytes but also splenic cells of BALB/c mice, whereas a moderate concentration (3 microg/ml) of Con A induced proliferation of these cells. A high concentration of Con A also induced the death of splenic cells of athymic BALB/c-nu/nu mice and the bone marrow cells of BALB/c mice which mainly consist of non-T cells. However, any concentration (1-30 microg/ml) of Con A failed to induce the proliferation of these cells. Specific binding of tetrameric Con A to mannose-containing receptors was required for the induction of cell death. DNA fragmentation was observed by both laser flow cytometry and electrophoresis in Con A-stimulated T cells and non-T cells. This indicated that the mechanism of induction of apoptosis with Con A is not necessarily TCR-dependent. Con A induced tyrosine phosphorylation of a number of proteins in various types of cells. Interestingly, phosphorylation of the 40 kDa protein developed only in the thymocytes and spleen cells that contain T cells, whereas phosphorylation of the 80 and 120 kDa proteins appeared in both T cells and non-T cells. These results suggested that the Con A-induced apoptosis of T cells and non-T cells involves different but possibly mutually related protein tyrosine phosphorylation-linked signals.

Animals↗
PubMed1996

Relationships between convulsive seizures and serum and brain concentrations of phenobarbital and zonisamide in mutant inbred strain EL mouse.

We evaluated the anticonvulsive effects of phenobarbital (PB) and zonisamide (ZNS) in the EL mouse, a strain that is highly susceptible to seizures. The concentration of each agent was analyzed in the serum and brain. PB suppressed the seizures dose-dependently, whereas even the higher dose of ZNS was ineffective in achieving a complete suppression. Serum and brain concentrations of these two drugs increased in proportion to the higher dose injected intraperitoneally. Brain concentration of PB was lower than the serum concentration, while the brain concentration of ZNS exceeded that in serum. Although serum concentration of ZNS was essential unchanged after the combined administration of PB and ZNS, the concentration of ZNS in brain tended to rise in proportion to the highly dose of PB. Combined administration was more effective than other treatment alone. Results indicated that brain concentration of ZNS especially after concomitant PB administration, were higher than that would be expected from the concentration of ZNS in serum.

Animals↗
PubMed1996

Cytokine-independent proliferation of IL-2-nonproducing CTL clones in association with high TCR-signal transduction responses.

Alloreactive CTL clone D2-23 proliferated in response to antigenic cells without IL-2 production. Among subclones of D2-23, the F1 but not F2 clone proliferated in response to soluble aCD3 or PMA, although both clones proliferated in response to immobilized aCD3, antigenic cells or soluble aCD3 plus costimulatory cells. The difference in responsiveness between F1 and F2 was not caused by distinct expression of CD3 or Fe receptors. Cyclosporin A, which totally blocks IL-2 production of Th1 cells, barely or only partially inhibited PMA- or aCD3-induced proliferation of F1. F1 did not produce cytokines for proliferation of F2 in response to soluble aCD3. Tyrosine phosphorylation developed for various proteins of F1 and F2 at the levels apparently correlated to the extent of cell proliferation when the cells were stimulated with soluble aCD3 or PMA. The proliferative responsiveness of F1 and F2 to the described stimulators was maintained by stimulation with IL-2 plus antigenic cells, or even IL-2 alone, but was decreased during resting culture or by stimulation with immobilized aCD3. These results show evidence of a new TCR-linked mechanism for CTL proliferation that is independent of costimulatory cell- or cytokine-mediated signaling, but is originally prepared by prior stimulation with IL-2.

Animals↗
PubMed1996

Age differences of psychiatric inpatients presenting with physical complications.

We reviewed the records of 292 inpatients in the psychiatric ward of Kagoshima University Hospital who were referred from other medical facilities over a 5-year period in order to clarify age differences in the reason for referral. Patients were classified into groups of physically and mentally ill individuals based on indications for admission. Both groups were further divided into four subgroups based on age. The incidence of inpatients with physical illnesses increased with age. Conditions related to pregnancy, childbirth and the puerperium occurred at high frequency in female patients in the 20- to 39-year-old subgroup. Individuals in the 40- to 59-year-old and in the > or = 60 years subgroups suffered more frequently from neoplasms. The proportion of patients manifesting a defective state in all age subgroups with the exception of the under 19-year-old subgroup was significantly higher in the physical illness group than in the mental illness group. The proportion of patients in a depressive state in the > or = 60 years subgroup was significantly higher in the mental illness group than in the physical illness group. Hence, it is necessary to find a method to be able to cope with psychiatric patients with physical complications to solve this problem.

Adult↗
PubMed1995

TCR-independent induction of low responsiveness by chemically fixed cells in alloreactive CTL clones and its prevention through cognate cell-cell interaction.

We established BALB/c-derived CD8+ CTL clones D2-22 (V beta 6+), D2-23 (V beta 8+) and D2-24 (V beta 8+) specific for B10.D2 minor H antigen. D2-22 and D2-23 proliferated without producing IL-2 in response to X-ray-irradiated antigenic cells, Con A, aCD3, PMA and IL-2. Paraformaldehyde-fixed antigenic spleen cells neither induced proliferation in the presence of costimulatory cells nor inhibited responses to irradiated antigenic cells added simultaneously. Unlike the previously reported results with IL-2-producing CTL clones and Th1 clones, the fixed antigenic cells failed to induce antigen-specific unresponsiveness in these IL-2-non-producing CTL clones. Instead, the responsiveness of these clones to fresh stimulation was found to be reduced severely after 2 days in the culture added with either antigenic or syngeneic fixed cells. Induction of their antigen-nonspecific low responsiveness by the fixed cells was prevented by adding irradiated syngeneic cells into the culture or even by increasing the concentration of responder D2-23 cells. Close contact of D2-23 and irradiated syngeneic cells was required to prevent the reduction of the responsiveness, although this cognate cell-cell interaction could be replaced by exogenously added IL-2 or PMA. Cytolytic and tumor cell growth inhibitory activities of D2-23 were also reduced by incubation with the fixed cells, which was prevented by the addition of irradiated syngeneic cells. These findings showed the unique properties of IL-2-nonproducing CTL clones in signal requirements for maintaining normal responsiveness for proliferation and cytolytic activity.

Animals↗
PubMed1995

Down-regulation of T-cell proliferation in response to soluble anti-CD3 antibodies through development of redirected cytolytic activity eliminating costimulatory cells.

CD4+ T-depleted spleen cells (CD8+ T cells) activated by anti-CD3 antibodies (aCD3) suppressed proliferation of CD8+ T-depleted spleen cells (CD4+ T cells) and fresh normal T cells in response to aCD3. Antigen-nonspecific cytolytic activity was induced in splenic CD8+ T cells by stimulation with aCD3 and showed the peak level on day 3, whereas cytolytic activity induced in CD4+ T cells was weak. Intact Ig but not F(ab')2 of aCD3 induced and mediated cytolytic activity. Correspondingly the cytolytic activity induced by aCD3 was directed against target cells bearing Ig-binding Fc-receptor activity and cytolysis was inhibited by the addition of free Ig into the assay system. We showed that aCD3-activated T cells carried a high level of aCD3 on their surface at the time after the peak proliferation when they attained high cytolytic activity. This raised the possibility that the anti-CD3-induced aCD3-redirected cytolytic activity eliminated Fc-receptor-bearing costimulatory cells in the culture for down-regulation of the T-cell proliferation. This view was supported by partial restoration of anti-CD3-induced low responsiveness of CD8+ T cells by the addition of fresh costimulatory cells. These results suggested a new pathway of down-regulation of T-cell proliferation by aCD3-activated cytolytic CD8+ T cells.

Animals↗
PubMed1994

Characterization of the immunoregulatory action of saikosaponin-d.

The immunoregulatory action of saikosaponin-d (SSd), which was isolated from the root of Bupleurum falcatum L. and has a steroid-like structure, was examined on splenic T lymphocytes of C57BL/6 mice. SSd displayed a definite action in vitro to bidirectionally control the growth response of T lymphocytes stimulated by concanavalin A, anti-CD3 monoclonal antibody, and calcium ionophore A23187 plus phorbol 12-myristate 13-acetate. Low concentrations (1-3 micrograms/ml) of SSd upregulated the responses to suboptimum stimuli of agonists, particularly during the relatively late stage of the responses, whereas it downregulated the responses to supraoptimal stimuli. Under appropriate experimental conditions, SSd promoted interleukin-2 (IL-2) production and IL-2 receptor expression. It also accelerated c-fos gene transcription, but it did not modulate the level of tyrosine phosphorylation of cellular proteins. We concluded from these results that SSd uniquely modulates T lymphocyte function and that at least one target of the action of SSd is located at or before the step of c-fos gene transcription and after T-cell receptor/CD3-mediated protein tyrosine kinase activation.

Adjuvants, Immunologic↗
PubMed1993

Glycyrrhizin as a promoter of the late signal transduction for interleukin-2 production by splenic lymphocytes.

Cellular and molecular mechanisms of the immunomodulatory action of glycyrrhizin (GL) were studied. We demonstrated that GL displays a unique action to prolong the duration of the T-cell receptor-mediated in vitro splenic T-lymphocyte growth response to anti-CD3 monoclonal antibody (mAb) or concanavalin A (Con A) through enhancement of interleukin-2 (IL-2) secretion and IL-2 receptor (IL-2R) expression. The augmentation by GL of IL-2 production was also found in spleen cells stimulated with A23187 plus phorbol 12-myristate 13-acetate (PMA), suggesting that GL primarily affects some post-receptor stage of the signal transduction. We also found that the time of GL action for promoting IL-2 production and growth response was 2 hr or more after receptor activation. Correspondingly, GL did not augment the anti-CD3 mAb or Con A-mediated protein tyrosine phosphorylation and c-fos transcription. We concluded from these results that GL acts as a promoter of the late signal transduction of T lymphocytes for IL-2 production.

Animals↗
PubMed1991

Preferential development of pre-B lymphomas with drastically down-regulated N-myc in the E mu-ret transgenic mice.

We established one transgenic mouse line which developed pre-B leukemic lymphomas by introducing ret cDNA driven by the SV40 promoter and the mouse immunoglobulin (Ig) enhancer. Lymphomas developed not only in the lymph nodes and the spleen but also in the thymus between the ages of 7 and 21 weeks. Analyses of cell surface phenotypes and Ig gene rearrangement revealed that these tumors were surface IgM-B220+ pre-B lymphomas. The rearrangement pattern of the Ig heavy chain locus indicated that the tumor cells were mono- or oligoclonal. Northern blot analysis showed that the ret transgene was expressed at a high level not only in the tumors but also in the prelymphomatous lymphoid tissues. We found that the expression of N-myc was dramatically down-regulated in the tumor cells, while the expression of c-myc was rather stable. Further experiments demonstrated that ret gene product did not directly down-regulate the expression of N-myc in transformed pre-B cell lines by in vitro transfection assay. From these results, we conclude that under the control of Ig enhancer, the ret transgene affected B lymphocytes at the early maturation stage as a prerequisite for transformation, preferentially generating a unique maturation stage of pre-B lymphomas whose N-myc expression was developmentally down-regulated.

Animals↗
PubMed1991

A possible site of in vivo action of cyclosporin A for transplantation immunity: comparative study with cyclophosphamide.

The immunosuppressive mechanisms of cyclosporin A (CsA) and cyclophosphamide (CPM) in vivo were studied by measuring the transplantation immunity for second set rejection of an allogeneic ascites tumor. The transplantation immunity in our assay system was mediated primarily by allospecific cytotoxic T lymphocytes (CTL). Our results showed that both CsA and CPM did not affect the process of inducing the immunity, but they inhibited the effector phase of that transplant immunity. The experiments using 51Cr-release assay in vitro on peritoneal exudate cells as effector cells showed that the effector phase of the transplantation immunity in vivo involved the maturation from immunological memory CTL-precursor cells to effector CTL with clonal expansion. Further, adoptive cell transfer experiments showed that CsA did not eliminate the immunological memory CTL nor induce the suppressor cells in donor mice. All the data suggested that the maturation of memory CTL precursor cells to effector CTL was inhibited by CsA which would block lymphokine production even in vivo, whereas CPM eliminated the CPM-sensitive memory CTL precursor cells. The findings that CsA and CPM act on the different sites of CTL maturation support the possibility of effectiveness of the combination therapy of the two agents for controlling the transplantation immunity.

Animals↗
PubMed1991

Characterization of the individual and cross-reactive antigens involved in the anti-tumor immunity induced by use of an H-2K-erbB recombinant gene transfectant.

The specificities of the antisera raised in the CDF1 mice that had been immunized with the P1.HTR tumor cells xenogenized by transfection with recombinant H-2Kb-erbB gene were studied. The antisera cross-reacted with a broad range of tumor cell lines maintained either in vitro or in vivo in an immunofluorescence assay. However, they did not react at all with syngeneic normal tissue cells from thymus, spleen, bone marrow and fetal liver. Even though antigens related to the murine leukemia virus and murine mammary tumor virus (MuMTV) were demonstrated in many of the tumor cell lines tested with specific antibodies, these antigens did not seem to be primarily involved in the anti-P1.HTR antibody activity. The 74 kDa molecule, which was precipitated by the anti-P1.HTR anti-serum from the surface radiolabeled cell extract of P1.HTR tumor and was discriminated from the 70 kDa molecule precipitated by the anti-MuMTV serum, was widely distributed among various tumor cell lines tested, but was absent in normal tissue cells. In contrast to the extensive cross-reaction by the antibody, the cytotoxic T lymphocyte generated in the P1.HTR immune mice were shown to be specific to the P1.HTR tumor, and the 98 kDa molecule was precipitated by the anti-P1.HTR serum from the P1.HTR tumor but not from other tumors tested. It is suggested from these results that the 98 kDa molecule is a candidate for an individual tumor-specific transplantation antigen, and is immunodominant for inducing cytotoxic T lymphocytes to coexisting intrinsic retroviral antigens and other serologically cross-reactive tumor antigens.

Animals↗
PubMed1991

Allotype-linked immune response genes: roles in network control of the immune system.

Studies on allotype-linked immune response genes and related genes are overviewed with particular attention to our current results in unique models. Significance of actions of various immune response genes in relation to allelic polymorphism of molecules in the immune system is discussed. The molecules involve immunoglobulins, T cell receptors, major histocompatibility complex and a number of cell interaction molecules, many of which belong to the immunoglobulin superfamily. Differential roles of V-linked and C-linked immune response genes for network control of the immune system, preparing the V structure repertoire, controlling antigen presentation and modulating the effector mechanism, are suggested.

Animals↗
PubMed1990

Cytotoxic T lymphocyte recognition of the H-2-erbB hybrid gene product lacking the complete H-2 domain structure.

The chimeric mouse MHC class I gene derived from a recombinant H-2Kb gene, in which the coding region for a large part of alpha 1 and alpha 2 extracellular domains was replaced with a partial avian erythroblastosis virus erbB gene segment encoding the kinase domain, was successfully introduced into a mouse mastocytoma line P1.HTR (H-2d) and transcribed to mRNA. The transfectant cells expressed the chimeric gene product, which was reactive to a phosphotyrosine-specific antibody. When the chimeric gene transfectant was inoculated into CDF1(H-2d) or BDF1(H-2d/b) mice, it grew at an early time but regressed thereafter. Transfectant-specific as well as parental P1.HTR-specific antibody activities were demonstrated in the sera of these mice. Transfectant-specific cytotoxic T lymphocytes (CTL) were generated in the antigen-sensitized culture of spleen cells from the transfectant-immune mice. The CTL-mediated lysis of target chimeric gene transfectant cells was poorly inhibited by anti-H-2d antiserum, which blocked the lysis of parental P1.HTR cells by anti-tumor CTL developed in parallel. The former was, however, inhibited by either anti-transfectant antiserum or anti-phosphotyrosine antibody, which was ineffective for blocking the latter. Target cell lysis by either anti-transfectant or anti-tumor CTL was blocked by anti-CD8 monoclonal antibody but not by anti-CD4 antibody. It was suggested from these results that the H-2K-erbB hybrid gene product, which lacks complete three-domain class I structure, was recognized by CTL in a manner that was endogenous H-2 class I-independent but CD8-dependent.

Animals↗