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Biomedical subjects

M Yanagita

Publications and source records attributed to M Yanagita.

At least 19 recordsLinked to original sources
PubMed2006

Modulator of bone morphogenetic protein activity in the progression of kidney diseases.

Tubular damage and interstitial fibrosis is a final common pathway leading to end-stage renal disease, and once tubular damage is established, it cannot be reversed by currently available treatment. The administration of bone morphogenetic protein-7 (BMP-7) in pharmacological doses repairs established tubular damages and improves renal function in several kidney disease models; however, pathophysiological role of endogenous BMP-7 and regulatory mechanism of its activities remain elusive. The activity of BMP is precisely regulated by certain classes of molecules termed BMP agonist/antagonist. In this review, roles of BMP agonist/antagonists possibly modulating the activity of BMP in kidney diseases are discussed. Our group demonstrated that uterine sensitization-associated gene-1 (USAG-1), a novel BMP antagonist abundantly expressed in the kidney, is the central negative regulator of BMP-7 in the kidney, and that mice lacking USAG-1 (USAG-1(-/-) mice) are resistant to kidney injuries. USAG-1(-/-) mice exhibited markedly prolonged survival and preserved renal function in acute and chronic renal injuries. Renal BMP signaling, assessed by phosphorylation of Smad proteins, is significantly enhanced in USAG-1(-/-) mice during renal injury, indicating that the preservation of renal function is attributed to enhancement of endogenous BMP-7 signaling. Furthermore, the administration of neutralizing antibody against BMP-7 abolished renoprotection in USAG-1(-/-) mice, indicating that USAG-1 plays a critical role in the modulation of renoprotective action of BMP, and that inhibition of USAG-1 will be promising means of development of novel treatment for kidney diseases.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Activation of adenosine-receptor-enhanced iNOS mRNA expression by gingival epithelial cells.

A series of reports has revealed that adenosine has a plethora of biological actions toward a large variety of cells. In this study, we investigated the influence of adenosine receptor activation on iNOS mRNA expression in human gingival epithelial cells (HGEC) and SV-40-transformed HGEC. HGEC expressed adenosine receptor subtypes A1, A2a, and A2b, but not A3 mRNA. Ligation of adenosine receptors by a receptor agonist, 2-chloroadenosine (2CADO), enhanced iNOS mRNA expression by both HGEC and transformed HGEC. In addition, the adenosine receptor agonist enhanced the production of NO(2)(-)/NO(3)(-), NO-derived stable end-products. An enhanced expression of iNOS mRNA and NO(2)(-)/NO(3)(-) was also observed when SV40-transformed HGEC were stimulated with CPA or CGS21680, A1- or A2a-selective adenosine receptor agonists, respectively. These results provide new evidence for the possible involvement of adenosine in the regulation of inflammatory responses by HGEC in periodontal tissues.

Adenosine↗
PubMed2001

HIV mucosal vaccine: nasal immunization with rBCG-V3J1 induces a long term V3J1 peptide-specific neutralizing immunity in Th1- and Th2-deficient conditions.

In the vaccine strategy against HIV, bacillus Calmette-Guérin (BCG), a live attenuated strain of Mycobacterium bovis, is considered to be one of potential vectors for mucosal delivery of vaccine Ag. We analyzed the induction of the Ag-specific Ab response by nasal immunization with recombinant BCG vector-based vaccine (rBCG-V3J1) that can secrete the V3 principal neutralizing epitope of HIV. Mice were nasally immunized with rBCG-V3J1 (10 microg) three times at weekly intervals. Four weeks after the initial immunization, high titers of V3J1-specific IgG Abs were seen in serum. These high levels of HIV-specific serum IgG responses were maintained for >12 mo following nasal immunization without any booster immunization. V3J1-specific IgG-producing cells were detected in mononuclear cells isolated from spleen, nasal cavity, and salivary gland of the nasally vaccinated mice. Nasal rBCG-V3J1 also induced high levels of prolonged HIV-specific serum IgG responses in Th1 (IFN-gamma(-/-))- or Th2 (IL-4(-/-))-immunodeficient mice. Further, IgG3 was highest among V3 peptide-specific IgG subclass Ab responses in these immunodeficient mice as well as in wild-type mice. In addition, this Ag-specific serum IgG Abs induced by nasal immunization with rBCG-V3J1 possessed the ability to neutralize clinical isolate of HIV in vitro. These results suggested that the nasal rBCG-V3J1 system might be used as a therapeutic vaccine in addition to a prophylaxis vaccine for the control of AIDS.

AIDS Vaccines↗
PubMed2001

CD11c(+)B220(+)Gr-1(+) cells in mouse lymph nodes and spleen display characteristics of plasmacytoid dendritic cells.

Human plasmacytoid dendritic cells (pDCs) are major producers of IFNalpha, are activated by CpG motifs, and are believed to enter lymph nodes (LNs) via L-selectin dependent extravasation across high endothelial venules. To identify a similar murine DC type, CD11c(+) cells in the LNs of L-selectin-deficient and control BALB/c mice were compared, revealing a population of CD11c(+)CD11b(-) cells that is reduced 85% in the LNs of L-selectin-deficient mice. These cells are Gr-1(+)B220(+)CD19(-), either CD4(+) or CD8(+), and localize within T cell zones of LNs. Freshly isolated CD11c(+)Gr-1(+) cells express major histocompatibility complex class II at low levels, display a plasmacytoid morphology, and survive poorly in culture. Their survival is increased and they develop a DC-like morphology in interleukin 3 and CpG. Like human pDCs, CD11c(+)Gr-1(+) cells stimulate T cell proliferation after activation with CpG and produce IFNalpha after stimulation with influenza virus. These cells also display a strain-specific variation in frequency, being fivefold increased in the LNs of BALB/c relative to C57BL/6 mice. These CD11c(+)CD11b(-)B220(+)Gr-1(+) cells appear to be the murine equivalent of human pDCs.

Animals↗
PubMed2001

Gas6 induces mesangial cell proliferation via latent transcription factor STAT3.

Mesangial cell proliferation is essential for the pathogenesis and progression of glomerular disease. Previously, we showed that Gas6 plays a pivotal role in mesangial cell proliferation in vitro and in vivo. In the present study, we identified downstream targets of Gas6 signaling to examine the role in mesangial cell proliferation in vitro and in vivo. We found that Gas6 tyrosine phosphorylates STAT3 (signal transducers and activators of transcription) with concomitant translocation to the nucleus and induces STAT3-dependent transcriptional activation in cultured mesangial cells. Expressing dominant negative STAT3 inhibited Gas6-mediated transcriptional activation of STAT3 and abolished Gas6-induced mesangial cell proliferation. In a model of mesangial proliferative glomerulonephritis, STAT3 is phosphorylated in mesangial cells, and its phosphorylation peaks at day 8 after the injection of anti-Thy1.1 antibody. Inhibition of Gas6 by warfarin and the extracellular domain of its receptor, Axl, abolished phosphorylation of STAT3 in vivo. Thus, our in vitro and in vivo findings indicate that autocrine growth factor Gas6 induces mesangial cell proliferation via latent transcription factor STAT3. Therefore, STAT3 might be a new therapeutic target for kidney disease induced by mesangial proliferation.

Animals↗
PubMed2001

Gas6 regulates mesangial cell proliferation through Axl in experimental glomerulonephritis.

Proliferation of mesangial cells is a hallmark of glomerular disease, and understanding its regulatory mechanism is clinically important. Previously, we demonstrated that the product of growth arrest-specific gene 6 (Gas6) stimulates mesangial cell proliferation through binding to its cell-surface receptor Axl in vitro. We also showed that warfarin and the extracellular domain of Axl conjugated with Fc portion of human IgG1 (Axl-Fc) inhibit mesangial cell proliferation by interfering the Gas6/Axl pathway in vitro. In the present study, therefore, we examined in vivo roles of Gas6 and Axl in an experimental model of mesangial proliferative glomerulonephritis induced by the injection of anti-Thy1.1 antibody (Thy1 GN). In Thy1 GN, expression of Gas6 and Axl was markedly increased in glomeruli, and paralleled the progression of mesangial cell proliferation. Administration of warfarin or daily injection of Axl-Fc inhibited mesangial cell proliferation, and abolished the induction of platelet-derived growth factor-B mRNA and protein in Thy1 GN. Moreover, the anti-proliferative effect of warfarin was achieved at lower concentrations than those in routine clinical use. These findings indicate that the Gas6/Axl pathway plays a key role in mesangial cell proliferation in vivo, and could be a potentially important therapeutic target for the treatment of renal disease.

Animals↗
PubMed2000

Interaction of sphingosine 1-phosphate with plasma components, including lipoproteins, regulates the lipid receptor-mediated actions.

The concentration of sphingosine 1-phosphate (S1P) in plasma or serum is much higher than the half-maximal concentration of the sphingolipid needed to stimulate its receptors. Nevertheless, the inositol phosphate response to plasma or serum mediated by Edg-3, one of the S1P receptors, which was overexpressed in Chinese hamster ovary cells, was much smaller than the response expected from the total amount of S1P in these samples. The inositol phosphate response to exogenous S1P was markedly attenuated in the presence of charcoal-treated low-S1P serum. The inhibitory effect was lost by boiling but not by dialysis of the serum. The inhibitory action of the serum was specific to S1P and was associated with the trapping of exogenous S1P; the inositol phosphate response to P(2)-purinergic agonists was somewhat enhanced by the charcoal-treated serum. Among the components of plasma or serum, lipoproteins such as low-density and high-density lipoproteins showed a stronger activity for trapping S1P than lipoprotein-deficient serum. Consistent with this observation, we detected a 15-100-fold higher amount of S1P per unit amount of protein in lipoproteins than in the lipoprotein-deficient serum. Thus even though the protein content of the lipoprotein fraction contributes to only 4% of the total protein content of plasma or serum, more than 60% of S1P is distributed in this fraction. These results suggest that the tight binding of S1P to the components of serum or plasma, including lipoproteins, may interfere with the S1P binding to its receptors and thereby attenuate the lipid-receptor-mediated actions in the cells.

Animals↗
PubMed2000

IL-15 and IL-15 receptor selectively regulate differentiation of common mucosal immune system-independent B-1 cells for IgA responses.

We show in this report a new regulatory role for IL-15 and IL-15R in the development of B-1 cells and their differentiation into IgA-producing cells. Mucosal IgA levels were found to be inhibited by anti-IL-15 mAb treatment in vivo, but enhanced by administration of rIL-15, while serum IgA levels remained unaffected. Mucosal B-1 cells preferentially proliferated in response to IL-15 in vitro. When mucosal B-1 and B-2 cells were separated into surface (s)IgM(+)sIgA(-) and sIgM(-)sIgA(+) fractions, IL-15R-specific mRNA was found to be predominant in both sIgM(+)sIgA(-) and sIgM(-)sIgA(+) B-1 cells at a much higher level than B-2 cells. Further, incubation of these different subsets of B-1 and B-2 cells with IL-15 resulted in greater enhancement of the corresponding receptor expression by B-1 subset when compared with B-2 fraction. Interestingly, de novo isolated sIgM(+)sIgA(-) B-1, but not sIgM(+)sIgA(-) B-2, cells were already class-switched cells because the germline Calpha transcript was detected and was then further enhanced by IL-15. IL-15 also supported differentiation of both sIgM(+)sIgA(-) and sIgM(-)sIgA(+) B-1 cells into IgA-producing cells. Taken together, these findings suggest that IL-15 is a critically important cytokine for the differentiation of both sIgM(+),IgA(-) and sIgM(-)sIgA(+) B-1 cells expressing IL-15R into IgA-producing cells in mucosal tissues.

Animals↗
PubMed2000

Unilateral middle cerebral artery stenosis in an adult with Down's syndrome--case report.

A 29-year-old male with Down's syndrome presented with severe headache and vomiting. Computed tomography demonstrated subarachnoid hemorrhage. Left carotid angiography showed severe stenosis of the middle cerebral artery 2 cm distal to its origin, as well as abnormal hyper-vascularization near the stenosis site similar to that seen in moyamoya disease. Right carotid angiography showed no abnormalities. However, slight stenosis of the distal part of the bilateral vertebral arteries was noted. There was no aneurysm. We judged that the subarachnoid hemorrhage had been caused by rupture of the moyamoya-like vessel. Some patients with Down's syndrome have anatomical vascular abnormality and vascular fragility. The cerebral vascular abnormality found in this case may be part of the systemic vascular abnormalities associated with Down's syndrome. The vascular changes in some adult patients with Down's syndrome may be a sign of premature aging, and long-term studies with periodic vascular examination of patients with Down's syndrome need to be performed.

Adult↗
PubMed2000

Unique characteristics of lacrimal glands as a part of mucosal immune network: high frequency of IgA-committed B-1 cells and NK1.1+ alphabeta T cells.

PURPOSE: Immunologic characterization of IgA-committed B-1 and B-2 cells, and unique subsets of T cells isolated from the murine lacrimal gland (LG), the primary exocrine tissue for the ocular surface, which is considered to be a part of the mucosal immune system. METHODS: Single cells were obtained from LGs of C57BL/6 mice by the enzyme dissociation method using collagenase type IV. Samples underwent flow cytometric analysis to characterize the unique subsets of T and B cells. To test the effectiveness of ocular vaccination, mice were immunized ocularly or nasally with cholera toxin (CT; 10 microg/mouse) suspended in phosphate-buffered saline. Antigen-specific immune responses were determined by isotype and CT-specific enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immunospot (ELISPOT) assay. RESULTS: When mononuclear cells (MC) isolated from LG samples were examined by flow cytometry, approximately 28% of cells were characterized as B220+ B cells. Because surface IgA+ (sIgA+) B cells develop from B-1 and B-2 lineages, it was important to examine which subset of B cells gives rise to LG sIgA+ B cells. Examination of the MC isolated from LG samples showed that approximately 4% of cells were sIgA+ B cells. Furthermore, nearly all these sIgA+ B cells (97.5%) belonged to the B-1 lineage, especially the B-1a cell line (B220low, CD5+). Of the isolated CD3+ T cells, 75% were alpha(beta) and 25% were gamma(delta)T-cell receptor positive. The proportion of NK1.1+ alpha(beta) T cells was higher (3%) in LG samples than in submandibular gland samples (0.5%). Ocular immunization with CT-induced antigen-specific mucosal (e.g., found in tear-wash and saliva samples) and systemic (e.g., serum) immune responses. The magnitude of antigen-specific antibody responses was comparable to those induced by nasal immunization. CONCLUSIONS: These results show that LG contains unique subsets of B (e.g., sIgA+ B-1 cells) and T (e.g., NK1.1+ alpha(beta)T cells) cells. Furthermore, as a part of the mucosal immune barrier, the LG is an important immunologic tissue for the ocular surface.

Animals↗
PubMed1999

Nasopharyngeal-associated lymphoreticular tissue (NALT) immunity: fimbriae-specific Th1 and Th2 cell-regulated IgA responses for the inhibition of bacterial attachment to epithelial cells and subsequent inflammatory cytokine production.

To investigate the antibacterial activity of mucosal Th1 and Th2 immune responses induced nasally and orally, mice were immunized with mucosal vaccine containing fimbrial protein of Porphyromonas gingivalis, a causative agent for a destructive chronic inflammation in the periodontium, and cholera toxin (CT) as mucosal adjuvant. Nasal vaccine containing low doses of fimbriae (10 micrograms) and CT (1 microgram) induced Ag-specific Th1/Th2-type response in CD4+ T cells in mucosal effector tissues, including nasal passage and submandibular glands, which accounted for the generation of Ag-specific IgA-producing cells. In contrast, oral immunization required higher amounts of fimbriae and CT for the induction of Ag-specific IgA responses. Fimbriae-specific IgA mAbs generated from submandibular glands of nasally immunized mice inhibited P. gingivalis attachment to and reduced subsequent inflammatory cytokine production from epithelial cells. These findings suggest that nasal vaccination is an effective immunization regimen for the induction of Ag-specific Th1 and Th2 cell-driven IgA immune responses that possess the ability to inhibit bacterial attachment to epithelial cells and subsequent inflammatory cytokine production.

Animals↗
PubMed1999

Deficiency of IL-5 receptor alpha-chain selectively influences the development of the common mucosal immune system independent IgA-producing B-1 cell in mucosa-associated tissues.

Deletion of IL-5R alpha-chain (IL-5R alpha-/-) selectively influenced the mucosal IgA responses in vivo. While levels of IgA in mucosal secretions were more reduced in IL-5R alpha-/- mice than in wild-type mice, the levels of IgA in serum were not changed. The frequency of IgA-producing cells was reduced in mucosal effector sites (e.g., intestinal lamina propria and nasal passage), but not in inductive sites such as Payer's patches and nasal-associated lymphoreticular tissues in IL-5R alpha-/- mice. IgA-committed (surface IgA+; sIgA+) B-1 cells mainly resided in mucosal effector tissues, while conventional sIgA+ B (B-2) cells formed in mucosal inductive sites of wild-type mice. In contrast, in the effector tissue of IL-5R alpha-/- mice, sIgA+ B-1 cells, but not sIgA+ B-2 cells in the inductive site, were significantly reduced. IL-5R alpha was more expressed on sIgA+ B-1 cells than was IL-6R, while both IL-5R alpha and IL-6R were expressed on sIgA+ B-2 cells in wild-type mice. sIgA+ B-1 cells produced high levels of IgA with rIL-5 rather than of rIL-6 in vitro. Taken together, the findings suggest that the IL-5/IL-5R signaling pathway is critically important for the development of common mucosal immune system independent sIgA+ B-1 cell in mucosal effector tissues in vivo.

Animals↗
PubMed1999

Mechanism of inhibitory effect of warfarin on mesangial cell proliferation.

Because proliferation of mesangial cells is a hallmark of glomerular diseases, understanding the regulatory mechanism of mesangial proliferation is important for the treatment. Warfarin has long been used to treat glomerular diseases, although its mechanism of effect on mesangial proliferation has remained unknown. Therefore, this study was conducted to examine whether warfarin can inhibit mouse mesangial cell proliferation by focusing on Gas6, which has been shown to be activated by vitamin K-dependent gamma-carboxylation. In mesangial cells, Gas6 and its receptor Axl were expressed. In addition, exogenous Gas6 phosphorylated Axl, activated extracellular signal-regulated kinase, and stimulated [3H]-thymidine incorporation in mouse mesangial cells. This study also examined whether endogenous Gas6 stimulates mesangial proliferation. Conditioned medium (CM) from serum-starved mesangial cells could stimulate [3H]-thymidine incorporation and phosphorylate extracellular signal-regulated kinase, whereas CM in the presence of warfarin could not. Simultaneous administration of vitamin K could cancel the inhibitory effect of warfarin. These results suggest that vitamin K-dependent growth factors in the CM are critical for mesangial proliferation. Addition of the extracellular domain of Axl to the CM inhibited its mitogenic effect on mesangial cells, suggesting that this vitamin K-dependent growth factor is Gas6. It is concluded that Gas6 is an endogenous mitogen in mesangial cells, and warfarin inhibits mesangial proliferation possibly by inhibiting gamma-carboxylation of Gas6. This study sheds light on the regulation of mesangial proliferation and may lead to a new therapeutic strategy for glomerular diseases.

Animals↗
PubMed1998

Deletion of bone marrow stromal cell antigen-1 (CD157) gene impaired systemic thymus independent-2 antigen-induced IgG3 and mucosal TD antigen-elicited IgA responses.

Bone marrow stromal cell Ag-1 (BST-1; CD157)-deficient mice were generated to examine the immunologic roles of the molecule in vivo. In BST-1(-/-) mice, the development of peritoneal B-1 cells was delayed, and CD38(low/-) B-lineage cells were increased in the bone marrow and spleen. Partial impairment of thymus-independent (TI-2) and thymus-dependent (TD) Ag-specific immune responses was noted in the systemic and mucosal compartments of BST-1(-/-) mice, respectively. Although serum Ig levels as well as TD and TI-1 Ag-specific systemic immune responses were normal, the TI-2 Ag-induced IgG3 response was selectively impaired. Oral immunization of BST-1(-/-) mice with cholera toxin, a potent TD Ag for the induction of IgA response, resulted in the poor production of Ag-specific Abs at the intestinal mucosa accompanied by the reduced number of Ag-specific IgA-producing cells in the lamina propria. These results indicate that BST-1 has roles in B cell development and Ab production in vivo.

ADP-ribosyl Cyclase↗
PubMed1998

Nasal immune system: distinctive Th0 and Th1/Th2 type environments in murine nasal-associated lymphoid tissues and nasal passage, respectively.

The nasal mucosa, an important arm of the mucosal immune system, is the first site of contact with inhaled antigens to induce an IgA response. A major aim of this study was to characterize the Th1 and Th2 cytokine expression of mucosal T cells residing in nasal-associated lymphoid tissue (NALT) and nasal passages (NP) as IgA inductive and effector sites, respectively, at the transcription and cellular levels. An application of single-cell reverse transcription-PCR for analysis of Th1 (IFN-gamma) and Th2 (IL-4 and IL-6) cytokine-specific mRNA revealed the presence of CD4+ T cells with a Th0 profile in NALT, while high numbers of Th2 cytokine-specific mRNA expressed by CD4+ T cells were noted in NP followed by Th1-type cells. NALT CD3+ CD4+ T cells of Th0 type have the capacity to become Th1- and/or Th2-type cells since their activation via the TCR-CD3 complex resulted in the expression of an array of Th1 and Th2 cytokines. CD3+ CD4+ T cells from NP, but not NALT, provide a helper function for the induction of antibody-forming cells including IgA isotype in B cell cultures. These findings suggest that NALT is characterized by a Th0 environment which can gain a Th1 and/or Th2 phenotype. In contrast, NP is considered to be a Th2 dominant site with some Th1 cells that can support the induction of IgA-producing cells.

Animals↗
PubMed1998

Meningotheliomatous meningioma accompanied by aspergillosis at the skull base.

A 73-year-old man was admitted because of right frontal headache and gradual loss of right visual acuity, which had been occurring for 1 year. He had been treated with corticosteroids under the diagnosis of retrobulbar optic neuritis at a nearby clinic. Magnetic resonance imaging (MRI) revealed a nodular lesion at the tuberculum sellae, which showed isointensity on T1-weighted images, iso- to low-intensity on T2-weighted images, and heterogeneous enhancement with Gd-DTPA. Meningioma was diagnosed, and surgery was performed but was limited to biopsy because of intraoperative detection of purulent inflammation of the nodule. Histologic examination revealed aspergillosis in a portion of the meningotheliomatous meningioma. The patient died of meningoencephalitis about 1 month after surgery in spite of extensive treatment with antifungal agents. MRI findings of meningioma and aspergillosis are similar, thus making preoperative diagnosis difficult. However, this case provides evidence that aspergillosis should be included in the differential diagnosis when a skull-base meningioma-like nodule is noted if sinusitis is revealed in the sphenoid sinus.

Aged↗