Biomedical subjects

Taku Sato

Publications and source records attributed to Taku Sato.

At least 19 recordsLinked to original sources

PubMed2006

Essential roles of DC-derived IL-15 as a mediator of inflammatory responses in vivo.

Interleukin (IL)-15 is expressed in a variety of inflammatory diseases. However, the contribution of dendritic cell (DC)-derived IL-15 to the development of diseases is uncertain. Using established models of Propionibacterium acnes (P. acnes)- and zymosan-induced liver inflammation, we observed granuloma formation in the livers of wild-type (WT) and RAG-2(-/-) mice but not in those of IL-15(-/-) mice. We demonstrate that this is likely caused by an impaired sequential induction of IL-12, IFN-gamma, and chemokines necessary for monocyte migration. Likewise, lethal endotoxin shock was not induced in P. acnes- and zymosan-primed IL-15(-/-) mice or in WT mice treated with a new IL-15-neutralizing antibody. In both systems, proinflammatory cytokine production was impaired. Surprisingly, neither granuloma formation, lethal endotoxin shock, nor IL-15 production was induced in mice deficient for DCs, and adoptive transfer of WT but not IL-15(-/-) DCs restored the disease development in IL-15(-/-) mice. Collectively, these data indicate the importance of DC-derived IL-15 as a mediator of inflammatory responses in vivo.

Animals↗

PubMed2006

Establishment of a novel B-cell lymphoma cell line with suppressed growth by gamma-secretase inhibitors.

A novel lymphoma cell line, designated TMD8 was established from cells of a patient with diffuse large B-cell lymphoma. TMD8 cells expressed HES1 mRNA, suggesting constitutive activation of Notch signaling. TMD8 cells expressed normal-sized Notch1 protein, and showed no mutations in the NOTCH1 gene. Cell growth was suppressed by gamma-secretase inhibitors (GSI). It was reported that GSI suppressed growth of T-cell acute lymphoblastic leukemia (T-ALL) cell lines, which frequently had NOTCH1 mutations. In addition to T-ALL, TMD8 is another unique cell line sensitive to GSI, and is useful to study effects of GSI in molecular targeting therapy.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Interleukin 15-dependent crosstalk between conventional and plasmacytoid dendritic cells is essential for CpG-induced immune activation.

The function of interleukin 15 (IL-15) in unmethylated CpG oligodeoxynucleotide (CpG)-induced immune responses remains unknown. Here, in response to CpG, both wild-type and natural killer cell-depleted mice produced IL-12 and became resistant to a lethal dose of Listeria monocytogenes. In contrast, CpG-treated IL-15-deficient mice produced little IL-12 and succumbed to L. monocytogenes. CpG-stimulated conventional dendritic cells (cDCs) were the main producers of both IL-15 and IL-12, but cDCs did not produce IL-12 in the absence of plasmacytoid DCs (pDCs). The cDC-derived IL-15 induced CD40 expression by cDCs. Interaction between CD40 on cDCs and CD40 ligand on pDCs led to IL-12 production by cDCs. Thus, IL-15-dependent crosstalk between cDCs and pDCs is essential for CpG-induced immune activation.

Animals↗

PubMed2006

Auditory fear conditioning and conditioned stress raise NO(3) level in the Amygdala.

BACKGROUND: The conditioned fear response is considered to be acquired by experimental animals when tone information is combined with that of an electrical foot shock (unconditioned stimulus) in the amygdala. Nitric oxide biosynthesized in the brain is reportedly involved in several kinds of learning. METHODS: In this study, we continuously monitored the NO(3)(-) level, as a marker of nitric oxide production, in the amygdala starting before the application of tone and electrical foot shock stimuli together (conditioned group) or the tone stimulus alone (control group) on day 1, until after the tone information was given (both groups) on day 2, using the in vivo microdialysis method. RESULTS: The NO(3)(-) level of the conditioned group was increased on both day 1 and day 2, while that of the control group was not elevated on either day. Freezing behavior was observed in the conditioned but not the control rats. CONCLUSIONS: Although the sources of NO(3)(-) remain uncertain, these results suggest that nitric oxide is associated with auditory fear conditioning and the response to a conditioned stimulus.

Acoustic Stimulation↗

PubMed2006

Chronic intraperitoneal injection of interferon-alpha reduces serotonin levels in various regions of rat brain, but does not change levels of serotonin transporter mRNA, nitrite or nitrate.

Interferon-alpha therapy is associated with a high rate of depression, but the pathophysiological mechanisms remain unclear. The purpose of the present study was to investigate the effects of i.p. administered interferon-alpha on monoaminergic neurotransmission in the brain. The levels of monoamines and associated metabolites were measured in various regions of the rat brain using a high-performance liquid chromatography-electrochemical detection system. The serotonin transporter mRNA levels were also measured using in situ hybridization. After 1 day, dopamine turnover was diminished in the cortex. Norepinephrine turnover was decreased in most regions tested after 4 days. However, these changes were transient. After 14 days, serotonin turnover was increased in the frontal cortex and hippocampus in rats given a dose of 20 000 IU/kg; in the frontal cortex, hippocampus, amygdala, thalamus, hypothalamus and brainstem in those on 200 000 IU/kg; and in the thalamus and hypothalamus in those on 2 000 000 IU/kg (all P < 0.05). However, 14-day treatment did not significantly change serotonin transporter mRNA levels. Next, the question of whether interferon-alpha affects monoamine levels via induction of nitric oxide (NO), was investigated. However, there were no changes in either NO2- or NO3-, as markers of NO production, in any brain regions after 14-day treatment. These results suggest that chronic peripheral administration of interferon-alpha induces metabolic changes in the central serotonin system. Further investigation is needed to determine exactly how this cytokine affects the central serotonin system and to assess whether a central serotonin abnormality is involved in interferon-induced depression.

Animals↗

PubMed2005

Breakdown of mucosal immunity in the gut and resultant systemic sensitization by oral antigens in a murine model for systemic lupus erythematosus.

Secreted IgA plays a pivotal role in the mucosal immunity to maintain the front line of body defense. We found that the level of fecal IgA was dramatically decreased in aged (NZB x NZW)F(1) (BWF(1)) mice developing lupus nephritis, whereas levels in similarly aged New Zealand Black (NZB) and New Zealand White (NZW) mice remained unchanged compared with young mice. The number of cells obtained from Peyer's patches was markedly decreased in aged BWF(1) mice. Aged BWF(1) mice showed increased susceptibility to pathogenic bacterial infection. Furthermore, oral administration of OVA failed to inhibit secondary IgG response induced by systemic immunization, suggesting defective oral tolerance in aged BWF(1) mice. A significant amount of orally administered OVA was incorporated directly into the intestinal lamina propria in aged BWF(1) mice whereas it was mainly localized in subepithelial domes and interfollicular region in Peyer's patches in young mice. T cells obtained from renal and pulmonary lymph nodes of aged BWF(1) mice that had been orally administered with OVA showed an Ag-specific T cell proliferation, whereas those from young BWF(1), aged NZB, and aged NZW mice did not. Interestingly, aerosol exposure to OVA of aged BWF(1) mice, which had been orally administered with the same Ag, provoked an eosinophil infiltration in the lung. These results demonstrate that mucosal immunity in the gut is impaired and oral Ags induce systemic sensitization instead of oral tolerance in the development of murine lupus.

Administration, Inhalation↗

PubMed2005

Amygdalic levels of dopamine and serotonin rise upon exposure to conditioned fear stress without elevation of glutamate.

Conditioned fear is an artificial stress, induced by a stimulus, such as a tone, that does not elicit fear in nature. This fear response is acquired by experimental animals when tone is combined with an unconditioned stimulus, such as electrical foot shock. The amygdala is considered to be the area involved in acquisition, consolidation and recall of fear. A series of previous pharmacological studies showed antagonists of dopamine D1 and D2, glutamate N-methyl-D-asparatate and (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors to prevent the acquisition of conditioned fear. However, little is known about the types of neurotransmitters released when conditioned fear is acquired and recalled. The present study was designed to continuously monitor changes in extracellular levels of glutamate, dopamine and serotonin in the amygdala, at the acquisition of conditioned fear on Day 1 and at fear recall in response to a tone as a conditioned stimulus on Day 2, using the in vivo microdialysis method. Glutamate was elevated only on Day 1, while dopamine and serotonin rose on both days. The periods of elevated dopamine and serotonin were longer on Day 1 than on Day 2. These results suggest that greater amounts of glutamate, dopamine and serotonin are necessary for acquisition than for recall of conditioned fear.

Amygdala↗

PubMed2005

Effects of intraperitoneal administration of IFN-alpha for one, four, and fourteen days on amino acid levels in various rat brain regions.

Interferon-alpha (IFN-alpha) therapy is strongly associated with certain adverse effects, but the pathophysiologic mechanism is unclear. The present study was designed to investigate the influence of peripherally administered IFN- alpha on amino acid levels in the brain. IFN-alpha was administered intraperitoneally (i.p.) once daily to rats, and their brains were extracted 24 h after the last injection. The levels of glutamate, glycine, taurine, gamma-aminobutyric acid (GABA), and arginine in homogenized samples of the frontal cortex, striatum, hippocampus, amygdala, thalamus, hypothalamus, cerebellum, and brainstem were determined. One day of IFN-alpha treatment induced no significant changes in any of these amino acids. After 4 days of injections, glutamate, glycine, taurine, and gamma-aminobutyric acid levels were significantly higher than those in the control frontal cortex, striatum, hippocampus, amygdala, and thalamus. However, most of these amino acids returned to approximately basal levels, or even lower, with 14-day treatment. Our results suggest that daily peripheral administration of IFN-alpha affects the metabolism of amino acids in the brain. Further studies are necessary to determine if these effects of IFN-alpha on cerebral amino acids are involved in the pathophysiology of IFN-alpha-induced depression.

Amino Acids↗

PubMed2005

Effects of intraperitoneally injected lithium, imipramine and diazepam on nitrate levels in rat amygdala.

Nitric oxide (NO) has been studied in relation to the etiologies of various neurologic and psychiatric diseases. However, little is known about whether clinically available psychotropic drugs affect the NO system in the brain. Using an in vivo brain microdialysis method, the effects of intraperitoneally administered lithium, imipramine and diazepam on levels of , a marker of in vivo NO production, were investigated in the rat amygdala. Lithium significantly reduced, while imipramine raised, levels as compared with controls. These observations suggest that lithium and imipramine induce opposite effects on NO-related systems in the brain.

Amygdala↗

PubMed2005

Medico-legal aspects of traumatic injury of the vertebrobasilar artery.

Based on our experiences with medico-legal autopsies, we analyzed traumatic injury of the vertebrobasilar artery (VBA) in traffic accident victims. VBA rupture occurred in six cases with traumatic medullary lesions, but in none with cervical cord injury. A relatively small external force applied to the head or neck can induce isolated traumatic subarachnoid hemorrhage (SAH), which accounts for approximately 11% of fatal head injuries. We examined the relationship between site of impact and site of vascular injury in 16 cases of isolated traumatic SAH. The results showed that the vertebral artery (VA) on the side of impact tended to be longitudinally injured in victims experiencing an external force equivalent to that of a fist punch to the head or face. There was no clear relationship between the site of impact and the site of vascular injury in victims who had sustained an external force greater than that of a fist punch. However, our results suggest that an external force causing rotation of the head was likely to cause tearing of the artery. In cases in which an external force equivalent to that of a fist punch was applied to the head, a raised blood alcohol level was a significant risk factor for artery rupture. Furthermore, a difference in the diameters of the left and right VAs was a risk factor for artery rupture. To determine why the VA, the most frequent site of arterial dissection, is also frequently the site of injury, we histologically examined normal and dissected VBAs. We also discuss medico-legal issues of the causal relationship between external force applied and rupture or dissection of the VA.

Basilar Artery↗

PubMed2004

Endocrine disruptors (environmental estrogens) enhance autoantibody production by B1 cells.

Accumulating data suggest that endocrine disruptors affect not only the reproductive system, but also the immune system. We demonstrate here that endocrine disruptors including diethylstilbestrol (DES) and bisphenol-A (BPA) enhance autoantibody production by B1 cells both in vitro and in vivo. BWF1 mice, a murine model for systemic lupus erythematosus (SLE), implanted with Silastic tubes containing DES after orchidectomy developed murine lupus characterized by immunoglobulin G (IgG) anti-DNA antibody production and IgG deposition in the glomeruli in the kidney as well as those implanted with 17beta-estradiol (E2). Plaque-forming cells (PFC) producing autoantibodies specific for bromelain-treated red blood cells were significantly increased in mice implanted with DES and BPA. IgM antibody production by B1 cells in vitro was also enhanced in the presence of endocrine disruptors including DES and BPA. Estrogen receptor (ER) expression was upregulated in B1 cells in aged BWF1 mice that developed lupus nephritis. These results suggest that endocrine disruptors are involved in autoantibody production by B1 cells and may be an etiologic factor in the development of autoimmune diseases.

Animals↗

PubMed2004

Defective B1 cell homing to the peritoneal cavity and preferential recruitment of B1 cells in the target organs in a murine model for systemic lupus erythematosus.

We previously reported that B lymphocyte chemoattractant (BLC; CXCL13) was highly and ectopically expressed in aged (NZB x NZW)F1 (BWF1) mice developing lupus nephritis, and that B1 cells were preferentially chemoattracted toward BLC. We demonstrate in this study that B1 cells fail to home to the peritoneal cavity in aged BWF1 mice developing lupus nephritis, and that they are preferentially recruited to the target organs including the kidney, lung, and thymus when injected i.v. In contrast, B1 cells homed to the peritoneal cavity in aged BALB/c mice as effectively as in young mice. Accumulation of B1 cells to the omentum milky spots was also impaired in aged BWF1 mice compared with young mice. CD11bhighF4/80high cells with macrophage morphology were confirmed to be a major cell source for BLC in the peritoneal cavity both in young and aged BWF1 mice. However, the number of BLC-producing peritoneal macrophages was markedly decreased in aged BWF1 mice. These results suggest that the decreased number of BLC-producing peritoneal macrophages together with ectopic high expression of BLC in aged BWF1 mice result in abnormal B1 cell trafficking during the development of murine lupus.

Aging↗

PubMed2004

Aberrant B1 cell migration into the thymus results in activation of CD4 T cells through its potent antigen-presenting activity in the development of murine lupus.

B1 cells have different origin and function from conventional B (B2) cells and are considered to be involved in autoantibody production in the development of autoimmune disease. We found that B1 cells preferentially accumulated in the target organs including thymus in aged BWF1 mice, a murine model for systemic lupus erythematosus, and that B lymphocyte chemoattractant (BLC/CXCL13) expression was increased in the thymus before the onset of lupus nephritis, while stromal cell-derived factor-1 (SDF-1/CXCL12) and secondary lymphoid tissue chemokine (SLC/CCL21) expression remained unchanged. Adhesion molecules such as peripheral node addressin (PNAd), ICAM-1, and VCAM-1 were also expressed on endothelial cells in the enlarged thymic perivascular space (PVS) in aged BWF1 mice. BLC protein and PNAd were co-localized on these high-endothelial-venules-like vessels in enlarged PVS. B1 cells expressed higher level of costimulatory molecules and showed a potent antigen-presenting activity in allogeneic mixed lymphocyte reaction comparable to splenic dendritic cells. Interestingly, B1 cells stimulated proliferation of autologous thymic CD4 T cells in the presence of IL-2. These results indicate that aberrant B1 cell trafficking into the thymus due to ectopic high expression of BLC may result in an activation of self-reactive T cells in the development of murine lupus.

Age Factors↗

PubMed2004

Correlation of optical coherence tomography with angiography in retinal pigment epithelial detachment associated with age-related macular degeneration.

PURPOSE: To correlate optical coherence tomography (OCT) with angiographic signs of choroidal neovascularization (CNV) in retinal pigment epithelial detachment (PED) associated with age-related macular degeneration (ARMD). METHODS: Prospectively, the authors performed OCT in 35 eyes of 35 patients (30 men and 5 women with a mean age of 71.6 years [range, 56-76 years]) with ARMD. All 35 eyes had CNV in the area of PED or adjacent to it, which was shown by fluorescein or indocyanine green angiography. Cross-sectional images were obtained by the OCT scanning line through the CNV and PED. RESULTS: In 10 (56%) of 18 eyes in which the CNV was at the margin of the PED, a small PED was adjacent to the central, dome-shaped PED. There was a notch between the central and small mounds of PED. In 13 (76%) of 17 eyes in which the CNV was within the PED, a notch was seen in the dome-shaped PED, resulting in a contour with 2 mounds. One of the 2 mounds contained a highly reflective mass immediately beneath the detached retinal pigment epithelium in 8 (62%) of the 13 eyes. CONCLUSION: A tomographic notch in the PED may be diagnostically important as an indication of CNV beneath the detached retinal pigment epithelium in eyes with ARMD.

Aged↗

PubMed2004

Thalamic arteriovenous malformation with an unusual draining system--case report.

A 52-year-old man suddenly experienced headache and vomiting. Computed tomography demonstrated a small area of hemorrhage in the right cerebellar hemisphere. Angiography revealed a thalamic arteriovenous malformation (AVM) fed by the bilateral medial posterior choroidal arteries and left marginal tentorial artery, and drained into the confluence via the cerebellar veins without flow into the supratentorial venous system. The draining veins included two varices, one of which, in the right cerebellar hemisphere, was thought to be the source of bleeding. The AVM nidus was removed via the right occipital transtentorial approach. A portion of a drainer adhered to the surface of the great vein of Galen but without opening into the galenic system and all drainers from this thalamic AVM flowed into the infratentorial cerebellar venous system.

Cerebral Angiography↗

PubMed2004

Histological study of the normal vertebral artery--etiology of dissecting aneurysms.

Histological evaluation of dissecting aneurysms of the cerebral arteries has suggested that defects in the internal elastic lamina (IEL) induce dissection of the arterial wall. Dissecting aneurysms occur most frequently in the vertebral artery (VA). The present study examined sections of the normal VA to elucidate the mechanisms of arterial dissection. Bilateral VAs (20 vessels) were obtained from 10 patients who died of causes other than intracranial lesions. The VAs were detached from the VA union to the site 10 mm proximal from the point penetrating the dura mater. The VAs were cut at 5-mm intervals, and each segment was observed using modified Masson's trichrome staining for elastic fibers. The thickness of the media and adventitia significantly thinned after the origin of the posterior inferior cerebellar artery (PICA). IEL defects were observed at 35 sites in 11 vessels from six subjects. There was a high incidence of IEL defects in the extradural portion and near the origin of the PICA, areas frequently involved in arterial dissection. There was a high incidence of intimal thinning at areas of IEL defects (19 of 35), and thinning was particularly marked distal to the origin of the PICA. In the absence of intimal thickening, the vascular strength at the site of IEL defects may be reduced, which would promote the occurrence and progression of arterial dissection.

Adult↗

PubMed2003

Laminin-1 peptide-conjugated chitosan membranes as a novel approach for cell engineering.

Laminin, a major component of the basement membrane, has diverse biological activities. Recently, we identified various biologically active sequences on laminin-1 by using a large set of synthetic peptides. Chitosan, a polysaccharide, is biodegradable and has been used as a biomaterial. Here, we conjugated several biologically active laminin peptides onto chitosan membranes and measured the cell attachment activity of peptide-conjugated chitosan membranes with various cell types. The active laminin peptide-conjugated chitosan membranes promoted cell attachment with cell type specificity. A99 (AGTFALRGDNPQG)-chitosan membrane promoted cell attachment with well-organized actin stress fibers. This adhesion was inhibited by EDTA but not by heparin. AG73 (RKRLQVQLSIRT)-chitosan membrane promoted cell attachment with filopodia formation, and this adhesion was inhibited by heparin but not by EDTA. These data suggest that the A99-chitosan membrane interacted with an integrin cellular receptor and that the AG73-chitosan membrane promoted proteoglycan-mediated cell attachment, as previously reported. Furthermore, both AG73-chitosan and A99-chitosan membranes effectively promoted neurite outgrowth with PC12 rat pheochromocytoma cells. We conclude that conjugation on a chitosan membrane is applicable for testing quantitatively the biological activity of synthetic peptides and that these constructs have a potential ability to serve as bioadhesive materials for tissue regeneration and engineering.

Amino Acid Sequence↗

PubMed2003

Gene expression profile in human leukocytes.

Leukocytes are classified as myelocytic or lymphocytic, and each class of leukocytes consists of several types of cells that have different phenotypes and different roles. To define the gene expression in these cells, we have performed serial analysis of gene expression (SAGE) using human leukocytes and have provided the gene database for these cells not only at the resting stage but also at the activated stage. A total of 709,990 tags from 17 libraries were analyzed for the manifestation of gene expression profiles in various types of human leukocytes. Types of leukocytes analyzed were as follows: peripheral blood monocytes, colony-stimulating factor-induced macrophages, monocyte-derived immature dendritic cells, mature/activated dendritic cells, granulocytes, natural killer (NK) cells, resting B cells, activated B cells, naive T cells, CCR4(-) memory T cells (resting T(H)1 cells), CCR4(+) memory T cells (resting T(H)2 cells), activated T(H)1 cells, and activated T(H)2 cells. Among 38,961 distinct tags that appeared more than once in the combined total libraries, 27,323 tags were found to represent unique genes in certain type(s) of leukocytes. Using probability (P) and hierarchical clustering analysis, we identified the genes selectively expressed in each type of leukocytes. Identification of the genes specifically expressed in different types of leukocytes provides not only a novel molecular signature to define different subsets of resting and activated cells but also contributes to further understanding of the biologic function of leukocytes in the host defense system.

Databases, Factual↗