PubMed Health⌕ Search

Biomedical subjects

K Yoshizaki

Publications and source records attributed to K Yoshizaki.

At least 19 recordsLinked to original sources
PubMed2004

Blockade of interleukin-6 receptor suppresses reactive astrogliosis and ameliorates functional recovery in experimental spinal cord injury.

Endogenous neural stem/progenitor cells (NSPCs) have recently been shown to differentiate exclusively into astrocytes, the cells that are involved in glial scar formation after spinal cord injury (SCI). The microenvironment of the spinal cord, especially the inflammatory cytokines that dramatically increase in the acute phase at the injury site, is considered to be an important cause of inhibitory mechanism of neuronal differentiation following SCI. Interleukin-6 (IL-6), which has been demonstrated to induce NSPCs to undergo astrocytic differentiation selectively through the JAK/STAT pathway in vitro, has also been demonstrated to play a critical role as a proinflammatory cytokine and to be associated with secondary tissue damage in SCI. In this study, we assessed the efficacy of rat anti-mouse IL-6 receptor monoclonal antibody (MR16-1) in the treatment of acute SCI in mice. Immediately after contusive SCI with a modified NYU impactor, mice were intraperitoneally injected with a single dose of MR16-1 (100 microg/g body weight), the lesions were assessed histologically, and the functional recovery was evaluated. MR16-1 not only suppressed the astrocytic diffentiation-promoting effect of IL-6 signaling in vitro but inhibited the development of astrogliosis after SCI in vivo. MR16-1 also decreased the number of invading inflammatory cells and the severity of connective tissue scar formation. In addition, we observed significant functional recovery in the mice treated with MR16-1 compared with control mice. These findings suggest that neutralization of IL-6 signaling in the acute phase of SCI represents an attractive option for the treatment of SCI.

Analysis of Variance↗
PubMed2002

Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin-6 receptor monoclonal antibody in rheumatoid arthritis: a randomized, double-blind, placebo-controlled, dose-escalation trial.

OBJECTIVE: To investigate the safety and efficacy of MRA, a recombinant human anti-interleukin-6 (anti-IL-6) receptor monoclonal antibody of the IgG1 subclass that inhibits the function of IL-6, in patients with established rheumatoid arthritis (RA). METHODS: A randomized, double-blind, placebo-controlled, dose-escalation trial was conducted in 45 patients with active RA, as defined by the American College of Rheumatology (ACR) revised criteria. Patients were sequentially allocated to receive a single intravenous dose of either 0.1, 1, 5, or 10 mg/kg of MRA or placebo. The primary efficacy end point was meeting the ACR 20% response criteria at week 2 after treatment. RESULTS: Demographic features were similar between treatment groups. At week 2, a significant treatment difference was observed between the 5 mg/kg of MRA and placebo, with 5 patients (55.6%) in the MRA cohort and none in the placebo cohort achieving ACR 20% improvement. There was no statistically significant difference in the ACR 20% response between the other 3 MRA cohorts and placebo at week 2. The mean disease activity score at week 2 in those who received 5 mg/kg and 10 mg/kg of MRA was 4.8 and 4.7 (P < 0.001 and P < 0.001 by analysis of variance), respectively. These mean scores were statistically significantly lower than those in the 0.1- and 1-mg/kg MRA and the placebo cohorts (6.4, 6.2, and 7.0, respectively). The erythrocyte sedimentation rate and C-reactive protein values fell significantly in the 5- and 10-mg/kg MRA cohorts and normalized 2 weeks after treatment. Seventeen patients (5, 4, 6, 2, and 0 patients in the placebo, 0.1-, 1-, 5-, and 10-mg/kg MRA cohorts, respectively) required corticosteroid or disease-modifying antirheumatic drug treatment because of active disease before study end. They were regarded as nonresponders from the time they received these treatments. Diarrhea was the most common adverse event, occurring in 8% of patients. Seven patients (15.6%) reported a severe adverse event (3, 1, 2, and 2 patients in the placebo, 0.1-, 1-, and 10-mg/kg MRA cohorts). There were no serious adverse events that were thought to be related to the study drug. CONCLUSION: This is the first randomized controlled trial showing that inhibition of IL-6 significantly improved the signs and symptoms of RA and normalized the acute-phase reactants. Further research with multiple dosing is necessary to define the most appropriate therapeutic regimen of MRA in RA.

Acute-Phase Reaction↗
PubMed2002

Human single-chain Fv (scFv) antibody specific to human IL-6 with the inhibitory activity on IL-6-signaling.

Human anti-IL-6 antibody may be useful for the immunotherapy of various inflammatory diseases, such as rheumatoid arthritis. Since IL-6 is a growth factor for B cell hybridoma, it is not easy to isolate murine B cell hybridomas producing the anti-IL-6 antibody with the IL-6-signaling inhibitory activity. In this study, the antibody library (Vgamma-Vkappa, Vgamma-Vlambda, Vmu-Vkappa or micro-Vlambda ligated into the pCANTAB 5E phagemid vector) was prepared from peripheral blood mononuclear cells of 20 healthy subjects. The phage display library was panned with an IL-6-coated plastic plate, and the binding specificity was confirmed by ELISA and BIAcore. From the antibody library (Vgamma-Vlambda), five IL-6-specific phage clones were isolated. The effects of the soluble scFvs purified from these phage clones were tested on the growth of the IL-6-dependent human cell line, KT-3. Two of these clones significantly inhibited the growth of KT-3, and three showed no inhibition.

Amino Acid Sequence↗
PubMed2001

Humanized antibody to human interleukin-6 receptor inhibits the development of collagen arthritis in cynomolgus monkeys.

In the present study, we demonstrated the anti-arthritic effect of humanized anti-human IL-6 receptor (IL-6R) antibody, MRA, in cynomolgus monkey. MRA can react with monkey IL-6R and block signal transduction of IL-6. Collagen-induced arthritis (CIA) was induced by twice immunizing with bovine type II collagen (CII) emulsified with complete adjuvant. MRA was intravenously injected once a week, from the day of the first collagen immunization, for 13 weeks. The symptoms of arthritis were evaluated using a visual scoring system and radiography. Inflammatory parameters (C-reactive protein (CRP), fibrinogen, and erythrocyte sedimentation rate (ESR) and concentrations of anti-CII antibody, anti-MRA antibody, and MRA were monitored regularly. At the end of the study, histological evaluation was carried out. MRA, at a dose of 10 mg/kg, gave rise to statistically significant suppression. The elevation of serum CRP and fibrinogen levels and ESR were also inhibited. Furthermore, radiographic and histological examination showed that MRA treatment suppressed joint destruction. Our results demonstrate that IL-6 plays an important role in monkey CIA and that MRA may be an attractive agent for the treatment of rheumatoid arthritis.

Animals↗
PubMed2001

Effects of visual familiarity for words on interhemispheric cooperation for lexical processing.

The purpose of this study was to examine the effects of visual familiarity of words on interhemispheric lexical processing. Words and pseudowords were tachistoscopically presented in a left, a right, or bilateral visual fields. Two types of words, Katakana-familiar-type and Hiragana-familiar-type, were used as the word stimuli. The former refers to the words which are more frequently written with Katakana script, and the latter refers to the words which are written predominantly in Hiragana script. Two conditions for the words were set up in terms of visual familiarity for a word. In visually familiar condition, words were presented in familiar script form and in visually unfamiliar condition, words were presented in less familiar script form. The 32 right-handed Japanese students were asked to make a lexical decision. Results showed that a bilateral gain, which indicated that the performance in the bilateral visual fields was superior to that in the unilateral visual field, was obtained only in the visually familiar condition, not in the visually unfamiliar condition. These results suggested that the visual familiarity for a word had an influence on the interhemispheric lexical processing.

Adult↗
PubMed2001

CHOP, a basic leucine zipper transcriptional factor, contributes to the antiproliferative effect of IL-1 on A375 human melanoma cells through augmenting transcription of IL-6.

Interleukin-1 (IL-1) inhibits the proliferation of A375 human melanoma cells. We have demonstrated previously that p38 mitrogen-activated protein kinase (MAPK) mediated the antiproliferative effect of IL-1 partially through the downregulation of activity and protein level of ornithine decarboxylase (ODC). In this study, we investigated the role of CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), one of the p38 MAPK target transcriptional factors. The mRNA level of CHOP was not affected by IL-1 treatment in A375-6 cells. Unexpectedly, CHOP was constitutively phosphorylated, and IL-1 or p38 MAPK inhibitor, SB203580, did not affect the phosphorylation level. However, A375-6 cells exhibited enhanced sensitivity to IL-1 by transfecting CHOP expression plasmid and reduced sensitivity to IL-1 by antisense CHOP mRNA expression plasmid. Furthermore, CHOP appeared to regulate positively IL-6 production at the transcriptional level. The experiments using CHOP muteins revealed that dimerization ability - but not p38 MAPK-dependent phosphorylation or DNA binding activity - is important for the IL-6 inducing activity of CHOP. These results indicate that CHOP contributes to the IL-1 growth-inhibitory signal through augmenting IL-6 production.

Adjuvants, Immunologic↗
PubMed2001

Characterization of the human Fc gamma RIIB gene promoter: human zinc-finger proteins (ZNF140 and ZNF91) that bind to different regions function as transcription repressors.

Expression of the human low-affinity Fc receptors for IgG (human Fc gamma RII) is differentially regulated. We report here the characterization of the promoter structure of the human Fc gamma RIIB gene and the isolation of the promoter region-binding proteins by a yeast one-hybrid assay. The minimal 154-bp region upstream from the transcription start site of the human Fc gamma RIIB gene was shown to possess promoter activity in a variety of cells. An electrophoretic mobility shift assay indicated that multiple nuclear factors in cell extracts bind to the two regions [F2-3 (-110 to -93) and F4-3 (-47 to -31)] of the human Fc gamma RIIB gene promoter. Mutation analysis indicated that GGGAGGAGC (-105 to -97) and AATTTGTTTGCC (-47 to -36) sequences are responsible for binding to nuclear factors respectively. By using GGGAGGAGC and AATTTGTTTGCC as bait sequences, we cloned two zinc-finger proteins (ZNF140 and ZNF91) that bind to the F2-3 and F4-3 regions within the promoter of the human Fc gamma RIIB gene respectively. When the ZNF140 and ZNF91 were transfected with reporter plasmid, both showed repressor activity with additive effects. Thus, these results indicate that these cloned ZNF140 and ZNF91 proteins function as repressors for the human Fc gamma RIIB transcription.

5' Untranslated Regions↗
PubMed2001

Seven new bifuranocoumarins, dahuribirin A-G, from Japanese Bai Zhi.

Five new spirobifuranocoumarins, dahuribirins A-E (1-5) and two new bifuranocoumarins, dahuribirins F and G (6 and 7) were isolated from Japanese Bai Zhi (the root of Angelica dahurica Benth. et Hook. var. dahurica Benth. et Hook.) and their structures were established by chemical and spectral means.

Angelica↗
PubMed2001

Preferential and persistent activation of the STAT1 pathway in rheumatoid synovial fluid cells.

OBJECTIVE: Inflammatory cytokines such as interleukin 1 (IL-1), IL-6, and tumor necrosis factor-alpha are produced in great quantities in inflamed rheumatoid joints. However, little is known about the pathogenic significance of each cytokine in the proliferative synovitis and destruction of bone and joint. We investigated the role of cytokine receptor signals transduced into cells at the foci of rheumatoid inflammation. METHODS: Synovial fluid (SF) cells from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) were examined for the activation of a group of cytokine receptor signaling molecules, signal transducers and activators of transcription (STAT). RESULTS: DNA binding of STAT1 in SF cells was observed in 8 out of 14 patients with RA, but in none of the 10 patients with OA studied, and this was prevented by preincubation of these cells with neutralizing anti-IL-6 antibody. IL-6 activated both STAT1 and STAT3 in normal peripheral blood (PB) leukocytes, and preferentially STAT1 in rheumatoid SF cells. Moreover, STAT1 activation in rheumatoid SF cells appeared to be continuous, in contrast to the transient activation in normal PB leukocytes. CONCLUSION: STAT1 and STAT3 are differentially regulated in response to IL-6 in different cell types. The continuous STAT1 activation may be of pathogenic significance in the progression and persistence of RA.

Adult↗
PubMed2000

IL-6 is required for the development of Th1 cell-mediated murine colitis.

Proinflammatory cytokines have been demonstrated to play a crucial role in the pathogenesis of Crohn's disease. Among those cytokines, strong expression of IL-6 has been repeatedly demonstrated. To examine the role for IL-6 in the pathogenesis of Crohn's disease, we introduced anti-IL-6R mAb to a murine model of colitis. Colitis was induced in C.B-17-scid mice transferred with CD45RBhigh CD4+ T cells from BALB/c mice. Anti-IL-6R mAb or rat IgG was administered weekly after T cell transfer. ICAM-1 and VCAM-1 expression were analyzed by immunohistochemistry. Colonic cytokine expression was determined by RT-PCR. Mice treated with mAb showed normal growth, whereas controls lost weight. The average colitis score was 0.64 for mAb-treated mice and 1.80 for controls. T cell expansion in treated mice was less remarkable than in the controls. Colonic ICAM-1 and VCAM-1 expression were markedly suppressed by mAb. IFN-gamma, TNF-alpha, and IL-1beta mRNA were reduced by the treatment. The results presented here show a crucial role for IL-6 in the pathogenesis of murine colitis and suggest a therapeutic potential of anti-IL-6R mAb for treatment of human Crohn's disease.

Animals↗
PubMed2000

Signal transducer and activator of transcription 3 is required for glycoprotein 130-mediated induction of vascular endothelial growth factor in cardiac myocytes.

Activation of glycoprotein (gp) 130 transduces hypertrophic and cytoprotective signals in cardiac myocytes. In the present study, we have demonstrated that signals through gp130 increase the expression of vascular endothelial growth factor (VEGF) in cardiac myocytes via the signal transducer and activator of transcription (STAT) 3 pathway. After activation of gp130 with leukemia inhibitory factor (LIF), expression of VEGF mRNA rapidly increased with a peak at 3 h in cultured cardiac myocytes. Cardiotrophin-1 also enhanced VEGF mRNA expression in a dose-dependent manner. VEGF protein production and secretion to the medium were also enhanced by LIF and cardiotrophin-1 but not by interleukin-6. Adenovirus transfer of the dominant-negative form of STAT3 to cultured cardiac myocytes inhibited induction of VEGF expression induced by LIF, but neither PD98059 nor wortmannin was affected. In murine hearts, intravenous administration of LIF augmented expression of VEGF mRNA; however, the hearts of transgenic mice overexpressing dominant-negative STAT3 showed reduced expression of VEGF mRNA that was not induced after LIF stimulation. These data provide the first evidence that a STAT family protein functions as a regulator of angiogenic growth factors and suggest that gp130/STAT signaling in cardiac myocytes can control vessel growth during cardiac remodeling.

Animals↗
PubMed2000

Improvement in Castleman's disease by humanized anti-interleukin-6 receptor antibody therapy.

Castleman's disease, an atypical lymphoproliferative disorder, can be classified into 2 types: hyaline-vascular and plasma cell types according to the histologic features of the affected lymph nodes. The plasma cell type is frequently associated with systemic manifestations and is often refractory to systemic therapy including corticosteroids and chemotherapy, particularly in multicentric form. Dysregulated overproduction of interleukin-6 (IL-6) from affected lymph nodes is thought to be responsible for the systemic manifestations of this disease. Therefore, interference with IL-6 signal transduction may constitute a new therapeutic strategy for this disease. We used humanized anti-IL-6 receptor antibody (rhPM-1) to treat 7 patients with multicentric plasma cell or mixed type Castleman's disease. All patients had systemic manifestations including secondary amyloidosis in 3. With the approval of our institution's ethics committee and the consent of the patients, they were treated with 50 to 100 mg rhPM-1 either once or twice weekly. Immediately after administration of rhPM-1, fever and fatigue disappeared, and anemia as well as serum levels of C-reactive protein (CRP), fibrinogen, and albumin started to improve. After 3 months of treatment, hypergammaglobulinemia and lymphadenopathy were remarkably alleviated, as were renal function abnormalities in patients with amyloidosis. Treatment was well tolerated with only transient leukopenia. Histopathologic examination revealed reduced follicular hyperplasia and vascularity after rhPM-1 treatment. The pathophysiologic significance of IL-6 in Castleman's disease was thus confirmed, and blockade of the IL-6 signal by rhPM-1 is thought to have potential as a new therapy based on the pathophysiologic mechanism of multicentric Castleman's disease. (Blood. 2000;95:56-61)

Adult↗
PubMed2000

Effects on Rb(+)(K+) uptake of HeLa cells in a high K(+) medium of exposure to a switched 1.7 Tesla magnetic field.

Effects of a switched, time-varying 1.7 T magnetic field on Rb(+)(K+) uptake by HeLa S3 cells incubated in an isosmotic high K(+) medium were examined. The magnetic flux density was varied intermittently from 0.07-1.7 T at an interval of 3 s. K(+) uptake was activated by replacement of normal medium by high K(+) medium. A membrane-permeable Ca(2+) chelating agent (BAPTA-AM) and Ca(2+)-dependent K(+) channel inhibitors (quinine, charibdotoxin, and iberiotoxin) were found to reduce the Rb(+)(K+) uptake by about 30-40%. Uptake of K(+) that is sensitive to these drugs is possibly mediated by Ca(2+)-dependent K(+) channels. The intermittent magnetic field partly suppress ed the drug-sensitive K(+) uptake by about 30-40% (P < 0.05). To test the mechanism of inhibition by the magnetic fields, intracellular Ca(2+) concentration ([Ca(2+)]c) was measured using Fura 2-AM. When cells were placed in the high K(&plus;) medium, [Ca(2+)]c increased to about 1.4 times the original level, but exposure to the magnetic fields completely suppressed the increase (P < 0.01). Addition of a Ca(2+) ionophore (ionomycin) to the high K(+) medium increased [Ca(2+)]c to the level of control cells, regardless of exposure to the magnetic field. But the inhibition of K(+) uptake by the magnetic fields was not restored by addition of ionomycin. Based on our previous results on magnetic field-induced changes in properties of the cell membrane, these results indicate that exposure to the magnetic fields partly suppresses K(+) influx, which may be mediated by Ca(2+)-dependent K(+) channels. The suppress ion of K(+) fluxes could relate to a change in electric properties of cell surface and an inhibition of Ca(2+) influx mediated by Ca(2+) channels of either the cell plasma membrane or the inner vesicular membrane of intracellular Ca(2+) stores.

Calcium↗
PubMed2000

Human herpesvirus 8-encoded interleukin-6 homologue (viral IL-6) induces endogenous human IL-6 secretion.

We found that human herpesvirus 8-encoded IL-6 (vIL-6) induced endogenous human IL-6 (huIL-6) secretion from various cell lines (MT-4, THP-1, U937, Raji, and CESS) including patients with multicentric Castleman's disease. Especially, in MT-4 cells, huIL-6 was enhanced with vIL-6 by 30-fold compared with that of control. In addition, reverse transcriptase-polymerase chain reaction confirmed that vIL-6 induced huIL-6 expression in MT-4 cells. Our novel finding of the huIL-6 induction by vIL-6 indicates that vIL-6 may play a significant role in the pathogenesis of HHV-8 associated diseases.

Animals↗
PubMed2000

Enhanced expression and DNA binding activity of two CCAAT/enhancer-binding protein isoforms, C/EBPbeta and C/EBPdelta, in rheumatoid synovium.

OBJECTIVE: To investigate the activation and expression of CCAAT/enhancer-binding proteins (C/EBP), especially C/EBPbeta and -delta, in rheumatoid synovium, and their pathogenic implications in rheumatoid arthritis (RA). METHODS: The activation of C/EBPbeta and -delta was assessed in synovial tissues from patients with RA by electrophoretic mobility shift assay (EMSA); DNA binding activity of C/EBPs was evaluated by measuring EMSA band density. The expression and distribution of C/EBPbeta and -delta in synovial tissues were examined by immunohistochemistry analysis. As a control, synovial tissues from patients with osteoarthritis (OA) were studied. RESULTS: Enhanced DNA binding activity of C/EBPbeta and -delta, 2 major members of the C/EBP family, was detected in synovial tissues from RA patients, while synovial tissues from the patients with OA showed only faint or marginal activity (mean +/- SEM arbitrary units [AU] RA 23.3 +/- 11.7 in RA versus 4.5 +/- 1.3 in OA; P < 0.05). Moreover, the binding activities of the C/EBP proteins were correlated with both serum C-reactive protein levels (r = 0.62, P < 0.05) and synovial interleukin-6 messenger RNA levels (r = 0.60, P < 0.05). In immunohistochemistry studies, C/EBPbeta and -delta were detected predominantly in the rheumatoid synovial lining cells (both CD14+ and CD14- cells). CONCLUSION: C/EBPbeta and -delta may contribute to the pathology of rheumatoid synovitis.

Aged↗