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Biomedical subjects

K Yoshizaki

Publications and source records attributed to K Yoshizaki.

At least 19 recordsLinked to original sources
PubMed1999

Excessive extramedullary hematopoiesis in Cbfa1-deficient mice with a congenital lack of bone marrow.

Cbfa1, a transcriptional factor that belongs to the runt-domain gene family, plays a pivotal role in osteogenesis. Cbfa1-deficient mice completely lacked both intramembranous and endochondral bone formation owing to the maturational arrest of osteoblasts, resulting in a total lack of bone marrow throughout the entire skeleton. To investigate the development of hematopoiesis in Cbfa1-deficient mice, hematopoietic tissues and peripheral blood were examined. Colony-forming assays of yolk sac at embryonic day 10.5 (E10.5) and liver at E12.5 showed normal numbers of hematopoietic precursors in the mutant embryos. Further, histological examination and flow-cytometric analysis showed normal hematopoietic development of liver and spleen in the mutant embryos until E17.5. However, mutant embryos at E18.5 showed large hematopoietic foci in the periportal area of liver and mild splenomegaly with dilated vessels, and an increase of myeloid cells was observed in both organs. Flow-cytometric analysis also demonstrated a relative increase of granulocytes and a relative decrease of B-cells reciprocally in the livers and spleens of the mutant embryos. Colony-forming assays showed that the frequency of colony-forming unit-culture (CFU-C) was elevated in liver, and both the frequency and total number of CFU-C were increased in spleen of mutant embryos at E18.5. Moreover, leukoerythroblastosis was observed in peripheral blood of the mutant embryos. These data demonstrate that the congenital lack of bone marrow caused excessive levels of extramedullary hematopoiesis in both liver and spleen at the late embryonic stage.

Animals↗
PubMed1999

Anticytokine therapy in autoimmune diseases.

Autoimmune reaction and inflammation observed in autoimmune diseases may be caused by the deregulated production of cytokines. Interleukin-6 (IL-6) is a pleiotropic cytokine with a wide range of biological activities such as support of hematopoiesis, regulation of acute phase reactions, and generation of immune responses. Uncontrolled hyperproduction of IL-6 causes plasmacytosis, hyper-gamma-globulinemia, thrombocytosis, mesangial cell proliferation of the kidney as well as inflammatory symptoms which are frequently observed in autoimmune diseases. Thus, interference with IL-6 signal transduction may be useful for autoimmune disease therapy. The pathogenic significance of IL-6 in autoimmune disorders and new therapeutic approaches involving blocking of IL-6 signal transduction are discussed.

Animals↗
PubMed1998

Three distinct domains of SSI-1/SOCS-1/JAB protein are required for its suppression of interleukin 6 signaling.

Cytokine-inducible protein SSI-1 [signal transducers and activators of transcription (STAT)-induced STAT inhibitor 1, also referred to as SOCS-1 (suppressor of cytokine signaling 1) or JAB (Janus kinase-binding protein)] negatively regulates cytokine receptor signaling by inhibition of JAK kinases. The SSI family of proteins includes eight members that are structurally characterized by an SH2 domain and a C-terminal conserved region that we have called the SC-motif. In this study, we investigated the roles of these domains in the function of SSI-1. Results of reporter assays demonstrated that the pre-SH2 domain (24 aa in front of the SH2 domain) and the SH2 domain of SSI-1 were required for the suppression by SSI-1 of interleukin 6 signaling. Coexpression studies of COS7 cells revealed that these domains also were required for inhibition of three JAKs (JAK1, JAK2, and TYK2). Furthermore, deletion of the SH2 domain, but not the pre-SH2 domain, resulted in loss of association of SSI-1 with TYK2. Thus, SSI-1 associates with JAK family kinase via its SH2 domain, and the pre-SH2 domain is required for the function of SSI-1. Deletion of the SC-motif markedly reduced expression of SSI-1 protein in M1 cells, and this reduction was reversed by treatment with proteasome inhibitors, suggesting that this motif is required to protect the SSI-1 molecule from proteolytic degradation. Based on these findings, we concluded that three distinct domains of SSI-1 (the pre-SH2 domain, the SH2 domain, and the SC-motif) cooperate in the suppression of interleukin 6 signaling.

Amino Acid Sequence↗
PubMed1998

Effects of a time-varying strong magnetic field on transient increase in cytosolic free Ca2+ induced by bradykinin in cultured bovine adrenal chromaffin cells.

We tested the effects of exposure to a time-varying magnetic field changing between 0.07 and 1.7 T at an interval of 3 s on transient increase in intracellular Ca2+ stimulated by bradykinin in bovine adrenal chromaffin cells. Addition of bradykinin induced the increase in intracellular Ca2+ within a few minutes. The exposure to the magnetic field perfectly suppressed the increase in intracellular Ca2+ in Ca2+-free medium. The inhibition occurred for 15 min when the maximum magnetic flux density was more than 1.4 T. These results suggest that the exposure inhibits Ca2+ release from intracellular Ca2+ stores.

Animals↗
PubMed1998

Adrenomedullin stimulates interleukin-6 production in Swiss 3T3 cells.

Adrenomedullin (AM) has very recently been demonstrated to be produced and secreted from fibroblasts. The production of AM in the fibroblasts is augmented by inflammation-related substances, and Swiss 3T3 fibroblast cells express AM specific receptors coupled with adenylate cyclase. To assess the functions of AM secreted from fibroblasts, we measured the effect of AM on production in Swiss 3T3 cells of interleukin-6 (IL-6), a typical cytokine involved in the general inflammatory reactions. AM stimulated basal secretion of IL-6 5.5-fold, while other peptides elicited much weaker stimulatory effects. The effect of AM was inhibited with an AM receptor antagonist and a cAMP-dependent protein kinase (PKA) inhibitor. Furthermore, AM remarkably potentiated stimulatory effects of tumor necrosis factor-alpha, IL-1 beta and lipopolysaccharide on IL-6 production. This stimulatory effect of AM was induced through activation of gene transcription, which reached maximum within 30 min. These findings verify that AM is a rapid and extraordinarily potent regulator of IL-6 production in Swiss 3T3 cells acting through the cAMP-PKA pathway. The data thus obtained suggest that AM is a peptidergic regulator of inflammation.

3T3 Cells↗
PubMed1998

Deficient expression of Bruton's tyrosine kinase in monocytes from X-linked agammaglobulinemia as evaluated by a flow cytometric analysis and its clinical application to carrier detection.

The B-cell defect in X-linked agammaglobulinemia (XLA) is caused by mutations in the gene for Bruton's tyrosine kinase (BTK). Using the anti-BTK monoclonal antibody (48-2H), a flow cytometric analysis of intracytoplasmic BTK protein expressed in monocytes was successfully performed. To examine the possible identification of XLA patients and female carriers by this assay, we studied 41 unrelated XLA families with (35) or without (6) known BTK mutations. A flow cytometric assay showed deficient expression of the BTK protein in 40 of 41 patients, complete BTK deficiency in 35, and partial BTK deficiency in 5. One patient exhibited a normal level of BTK expression. All 6 patients with partial BTK deficiency or normal BTK expression had missense BTK mutations. The cellular mosaicism of BTK expression in monocytes from obligate carriers was clearly shown in 35 of 41 families. The results suggested that most BTK mutations in XLA might result in deficient expression of the BTK protein. We conclude that deficient expression of BTK protein can be evaluated by a flow cytometric assay, and the clinical usefulness and limitations in diagnosis of XLA patients and carriers are discussed.

Adolescent↗
PubMed1998

Treatment of rheumatoid synovitis with anti-reshaping human interleukin-6 receptor monoclonal antibody: use of rheumatoid arthritis tissue implants in the SCID mouse model.

OBJECTIVE: To examine the effect of anti-reshaping human interleukin-6 receptor monoclonal antibody (anti-rsHuIL-6R mAb) on patients with rheumatoid arthritis (RA), using SCID mice in which human RA synovial tissue has been grafted (SCID-HuRAg). METHODS: Tissue from human RA pannus was implanted subcutaneously in the backs of 69 SCID mice. Differences from human RA were examined pathologically. Anti-rsHuIL-6R mAb (100 microg) was administered intraperitoneally to mice once a week for 4 weeks. The implanted tissue was removed from the SCID-HuRAg mice on the fifth week after the initial treatment and examined pathologically. A group of SCID-HuRAg mice treated with control mAb, an auranofin-treated group, and an untreated group were used as controls. A total of 32 mice (8 in each group) were studied. RESULTS: Histologic characteristics of the implanted tissues in SCID-HuRAg mice were very similar to those of human RA even 2 months after implantation. In addition, the presence of CD4-, CD8-, CD20-, IL-6-, tumor necrosis factor alpha-, tartrate-resistant acid phosphatase (TRAP)-, matrix metalloproteinase 1 (MMP-1)-, and MMP-9-positive cells was confirmed by immunohistochemical staining. A significant decrease in the number of inflammatory cells, MMP-positive cells, and TRAP-positive cells was observed in the anti-rsHuIL-6R mAb treatment group as compared with the control groups. CONCLUSION: The SCID-HuRAg mouse is a useful model for evaluating the effectiveness of antirheumatic drugs. Anti-rsHuIL-6R mAb may have an antiinflammatory effect on RA synovitis and an inhibitory effect on osteoclasts.

Animals↗
PubMed1998

Blockage of interleukin-6 receptor ameliorates joint disease in murine collagen-induced arthritis.

OBJECTIVE: To clarify the role of interleukin-6 (IL-6) in the pathogenesis of collagen-induced arthritis (CIA). METHODS: CIA was induced by immunizing twice at a 3-week interval with bovine type II collagen (CII) emulsified with complete adjuvant. Rat anti-mouse IL-6 receptor (anti-IL-6R) monoclonal antibody MR16-1 or isotype-matched control antibody KH-5 was then injected once intraperitoneally. Symptoms of arthritis were evaluated with a visual scoring system, and serum anti-CII antibody and IL-6 levels were measured by enzyme-linked immunosorbent assay. In addition, the CII responsiveness of splenic lymphocytes from mice with CIA was examined. RESULTS: In mice with CIA, excess production of IL-6 in sera was observed within 24 hours after the first CII immunization, and then rapidly decreased. Serum IL-6 increased again beginning 14 days after immunization, in conjunction with the onset of arthritis. When MR16-1 was injected immediately after immunization with CII, it inhibited the development of arthritis in a dose-dependent manner. Furthermore, MR16-1-treated mice exhibited lower serum levels of IgG anti-CII antibody and reduced responsiveness of lymphocytes to CII. This suppressive effect was observed when MR16-1 was injected on day 0 or 3, but not when injected on day 7 or 14. CONCLUSION: IL-6 produced after CII immunization appears to play an essential role in the immunity to CII, and anti-IL-6R antibody reduces the development of CIA by suppressing IL-6 signal transduction.

Animals↗
PubMed1998

An electrophysiological study of pterygopalatine ganglion neurons in the rabbit.

A preparation was developed to investigate the synaptic connections of the pterygopalatine ganglion (P.P.G.) neurons of the rabbit. Many neurons received synaptic inputs from more than one preganglionic fiber in the vidian nerve (preganglionic nerve) with a wide range of conduction velocities. It is assumed that P.P.G. neurons integrate synaptic inputs from the higher centers. In some neurons. nicotinic fast excitatory postsynaptic potentials (e.p.s.p.s) were evoked in response to stimulation of one posterior nasal nerve, and also an antidromic action potential occurred in response to stimulation of the other posterior nasal nerve. Fast e.p.s.p.s were recorded from a ganglion neuron in response to the cooling stimulation of the nasal mucosa. These results revealed that the ganglionic reflex are mediated through the nasal afferent fibers exists in the P.P.G. Moreover, the appearance of slow inhibitory postsynaptic potentials (slow i.p.s.p.s) and slow excitatory postsynaptic potentials (slow e.p.s.p.s) in response to repetitive stimuli of the vidian nerve may influence the synaptic transmissions of P.P.G. neurons. The P.P.G. plays a significant role as a complicated key point of signal transmissions from both the periphery and higher centers.

Animals↗
PubMed1998

Intrathoracic multicentric Castleman disease: CT findings in 12 patients.

PURPOSE: To assess the computed tomographic (CT) findings of intrathoracic involvement in multicentric Castleman disease. MATERIALS AND METHODS: The study comprised 12 patients with lymph node biopsy-proved Castleman disease and multicentric involvement. The patients were aged 23-58 years (mean age, 42.9 years; five men, seven women). Seven patients underwent open lung biopsy (n = 3) or transbronchial lung biopsy (n = 4), which demonstrated lymphocytic interstitial pneumonitis. RESULTS: All patients had systemic symptoms, polyclonal hypergammaglobulinemia, and bilateral hilar and mediastinal lymph node enlargement. The nodes showed mild to moderate enhancement after intravenous administration of contrast material. At thin-section CT, all 12 patients showed poorly defined centrilobular nodules. Thin-walled cysts were present in 10 patients, thickening of the bronchovascular bundles in 10, and interlobular septal thickening in nine. Less common findings were subpleural nodules, ground-glass attenuation, air-space consolidation, and bronchiectasis. CONCLUSION: Multicentric Castleman disease is characterized by the presence of systemic symptoms, bilateral hilar and mediastinal lymphadenopathy, and centrilobular nodular opacities. The pulmonary parenchymal findings are due to the associated lymphocytic interstitial pneumonitis.

Adult↗
PubMed1997

Universal skew of T cell receptor (TCR) V beta usage for Crohn's disease (CrD).

It would be of clear interest and importance to identify T cell populations which correlate with the initiation of some T cell-mediated diseases; however, it is difficult to observe the initial response of T cells in these diseases because of modification due to immunosuppressive treatment. We investigated T cell receptor (TCR) V beta usage in both affected and unaffected mucosa from 16 patients with active Crohn's disease (CrD), undergoing nutritional therapy without any immunomodulatory medications. Semiquantitative reverse transcriptase-polymerase chain reaction showed increased expression of V beta 12 and 13 in the entire mucosa of CrD but not in the controls. This was confirmed by introducing a random cloning method. Such skewing was observed primarily in CD4+ lamina propria lymphocytes. DNA sequence analysis demonstrated a striking clonal expansion of V beta 12 T cells, but the dominant clones were not identical in the patients. These findings suggest the importance of superantigen as well as specific T cell response in the pathogenesis of CrD.

Adult↗
PubMed1997

Structure and function of a new STAT-induced STAT inhibitor.

The signalling pathway that comprises JAK kinases and STAT proteins (for signal transducer and activator of transcription) is important for relaying signals from various cytokines outside the cell to the inside. The feedback mechanism responsible for switching off the cytokine signal has not been elucidated. We now report the cloning and characterization of an inhibitor of STAT activation which we name SSI-1 (for STAT-induced STAT inhibitor-1). We found that SSI-1 messenger RNA was induced by the cytokines interleukins 4 and 6 (IL-4, IL-6), leukaemia-inhibitory factor (LIF), and granulocyte colony-stimulating factor (G-CSF). Stimulation by IL-6 or LIF of murine myeloid leukaemia cells (M1 cells) induced SSI-1 mRNA expression which was blocked by transfection of a dominant-negative mutant of Stat3, indicating that the SSI-1 gene is a target of Stat3. Forced overexpression of SSI-1 complementary DNA interfered with IL-6- and LIF-mediated apoptosis and macrophage differentiation of M1 cells, as well as IL-6 induced tyrosine-phosphorylation of a receptor glycoprotein component, gp130, and of Stat3. When SSI-1 is overexpressed in COS7 cells, it can associate with the kinases Jak2 and Tyk2. These findings indicate that SSI-1 is responsible for negative-feedback regulation of the JAK-STAT pathway induced by cytokine stimulation.

Amino Acid Sequence↗
PubMed1997

Myeloma biology and therapy. Present status and future developments.

Recent progress in cytokine studies has made it possible to understand the pathophysiological roles of cytokines in multiple myeloma. Specifically, interleukin (IL)-6 is a potent growth factor for myeloma cells and is also responsible for the progressive bone resorption characteristic of this disease. On the basis of this evidence, clinical trials to interfere with IL-6 signals have been initiated for the treatment of patients with advanced myeloma. Such a new therapeutic approach as well as myeloblative therapy should be able to provide us with the breakthrough needed to prevail over this so far incurable disease.

Antigens, CD↗
PubMed1997

Interleukin-6 secreting phaeochromocytoma associated with clinical markers of inflammation.

Phaeochromocytomas have been shown to produce not only catecholamines but other neuropeptides and hormones, with a variety of clinical manifestations. We report a 70-year-old female patient with phaeochromocytoma exhibiting sustained hypertension, low-grade fever, thrombocytosis, and elevated levels of plasma fibrinogen and C-reactive protein. Serum interleukin (IL)-6 levels were significantly elevated, whereas serum IL-1 alpha and IL-1 beta were not detectable. After surgical removal of the tumour, hypertension and low-grade fever disappeared, and the laboratory finding including serum IL-6 concentrations became normal. Immunohistochemical study of the tumour showed positive staining for IL-6. Culture of the resected tumour revealed the production of large amounts of IL-6. It is suggested that IL-6 secreted by the tumour was responsible for some of the clinical manifestations in this patient.

Adrenal Gland Neoplasms↗
PubMed1997

[Clinical application of interleukin-6 receptor antibody].

Interleukin-6 (IL-6) is a pleiotropic cytokine which shows multiple biological functions. Pathological significance of IL-6 has been elucidated in various diseases including multiple myeloma, Castleman's disease, and rheumatoid arthritis. Thus the blockade of IL-6 signal transduction may be therapeutically effective for these diseases. For this purpose, humanized anti-IL-6 receptor antibody was prepared, and its therapeutic efficacy has been examined. Immediately after administration of humanized anti-IL-y receptor antibody to the patients with multiple myeloma, fever and systemic edema disappeared followed by the stability of M-protein which had been rapidly increased before the treatment. Humaniged anti-IL-6 receptor antibody also improved not only the chronic inflammatory symptoms but also laboratory findings such a hemoglobin, C-reactive protein, erythrocyte sedimentation rate observed both in Castleman's disease and in rheumatoid arthritis. The data suggest that the blockade of IL-6 signal transduction can be a new therapeutic approach based on the pathological significance of IL-6 in these diseases.

Antibodies↗