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N Nishimoto

Publications and source records attributed to N Nishimoto.

At least 37 records · Page 2Linked to original sources
PubMed1999

Degenerate MAGGY elements in a subgroup of Pyricularia grisea: a possible example of successful capture of a genetic invader by a fungal genome.

The LTR-retrotransposon MAGGY is found sporadically in isolates of Pyricularia grisea (Magnaporthe grisea). Based on a dendrogram constructed by RFLP analysis of rDNA, isolates that carry MAGGY elements were classified into a single cluster that comprised four rDNA types. However, in a few members of this cluster, exemplified by isolates from common millet (Panicum miliaceum), the MAGGY element has distinct features. Southern analysis suggested that these isolates possessed a single copy of a MAGGY-related sequence whose restriction map differed from that of MAGGY itself. Sequence analysis revealed that the MAGGY-related sequence was a degenerate form of MAGGY, characterized by numerous C:G to T:A transitions, which have often been reported to result from RIP (Repeat-induced point mutation) or RIP-like processes. However, the favored target site for C:G to T:A transitions in this fungus, determined by examining a total of 501 sites, was (A/T)pCp(A/T), which differs from that for the RIP process originally reported in Neurospora (CpA), and from that reported in Aspergillus (CpG). The fact that certain members of the cluster of MAGGY carriers retain a single copy of a degenerate MAGGY element implies that the ancestor of these isolates successfully "captured" the invading MAGGY element.

Amino Acid Sequence↗
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↗
PubMed1999

[Advances in interleukin-6 therapy].

Interleukin-6 (IL-6) exhibits multiple biologic activities such as regulation of immunological responses and hematopoiesis, promotion of acute inflammation, and stimulation of some malignant and non-malignant cell growth. The IL-6 receptor system consists of an IL-6 specific binding molecule, IL-6R and a signal transducer, gp130. Following gp130 dimerization, IL-6 activates multiple signaling pathways (Ras dependent MAPk cascade, STAT1-STAT3 heterodimer pathway, and STAT3 homodimer pathway). Several other cytokines including oncostatin M, IL-11, leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF) and cardiotropin-1 (CT-1) use gp130 as a common signal transducing molecule and therefore have similar biological activities. Two major in vivo functions of IL-6 are reported. Firstly, IL-6 acts as a growth factor of some malignant and non-malignant cells such as malignant plasma cells in multiple myeloma, mesangial cells in the kidney, and keratinocytes. Secondly, IL-6 mediates inflammatory and immune responses in rheumatoid arthritis, Castleman disease, psoriasis, cardiac myxoma, cachexia, and other inflammatory conditions. Recently, a humanized anti-IL-6 receptor antibody was developed. Neutralization of IL-6 activity by the humanized anti-IL-6 receptor antibody may be a new therapeutic approach for IL-6 related diseases such as multiple myeloma, Castleman disease and rheumatoid arthritis.

Antibodies↗
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

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

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↗
PubMed1998

[New molecular prognostic markers in gastric carcinoma].

Many molecular events have been reported as prognostic factors in gastric cancer. Amplifications of K-sam and c-met genes are often associated with poorly differentiated adenocarcinoma, while ERBB2 genes are amplified in well--differentiated adenocarcinomas of the stomach. Alterations of tumor suppressor regulators confer progression of gastric cancer. On the other hand, multi autocrine loops of growth factors/receptors in gastric cancer cells play a key role in the progression and metastasis of cancer cells. The overexpression of K-sam gene, occurs in 31.9% of gastric cancers, and the prognosis of patients with overexpression of K-sam gene is poorer than those without it. Multivariate analysis reveals that the overexpression of K-sam gene is an important factor for prognosis, lymphnode metastasis and the depth of tumor invasion of gastric carcinomas.

Female↗
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

Correlation between expression of platelet-derived endothelial cell growth factor (thymidine phosphorylase) and microvessel density in early-stage human colon carcinomas.

Platelet-derived endothelial cell growth factor may play a role in tumor development through its angiogenic action. To clarify the relationship between expression of platelet-derived endothelial cell growth factor and microvessel density in the development of human colon carcinoma, we examined 80 early-stage colon carcinomas using microscopy and immunohistochemistry. Localization of platelet-derived endothelial cell growth factor was assessed by immunocytochemistry, while microvessel count was evaluated by either HE staining or Factor VIII immunostaining. Among the examined carcinomas, 35 were classified as m carcinomas including carcinoma in situ, whereas 45 were sm carcinomas. Fifteen (42.9%) of the 35 m and 30 (66.7%) of the 45 sm carcinomas demonstrated high vascular density, whereas 20 (57.1%) m and 15 (33.3%) sm carcinomas showed moderate or low vascular density. Vascular density was higher in sm carcinomas than in m carcinomas and there was a significant correlation between depth of invasion and vascular density. Of the 45 highly vascularized carcinomas, 44 expressed platelet-derived endothelial cell growth factor. There was a statistically significant correlation between the frequency of platelet-derived endothelial cell growth factor expression and microvessel density (P = 0.012). These data demonstrate that microvessel density may be associated with the depth of cancer invasion and that platelet-derived endothelial cell growth factor may play an important role in the early stage of colon cancer development through angiogenesis.

Carcinoma↗
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↗