[Steroid therapy and immunotherapy of patients with collagen diseases].
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Animals↗
Biomedical subjects
N Nishimoto
Publications and source records attributed to N Nishimoto.
Spermine suppresses the activation of human neutrophil NADPH oxidase in cell-free and semi-recombinant systems.
Spermine, a cellular polyamine, down-regulates O2- generation in human neutrophils stimulated by receptor-linked agonist [Ogata, Tamura and Takeshita (1992) Biochem. Biophys. Res. Commun. 182, 20-26]. In this study, to elucidate the mechanism for the inhibition, the effect of spermine on cell-free activation of the O2- generating enzyme (NADPH oxidase) was examined. Spermine suppressed the SDS-induced activation of NADPH oxidase in a dose-dependent manner with an IC50 of 18 microM. The inhibition was specific for spermine over its precursor amines, spermidine and putrescine. Spermine did not alter the Km for NADPH or the optimal concentration of SDS for activation. The amine was inhibitory only when added before activation, indicating that it affects the activation process rather than the enzyme's activity. An increased concentration of cytosol partly prevented the inhibition by spermine. In semi-recombinant cell-free system, spermine inhibited the activation of NADPH oxidase as effectively as in the cell-free system (IC50 = 13 microM). Pretreatment of each recombinant cytosolic component with spermine revealed that they (especially p67phox) are sensitive to spermine. These results suggest that spermine interacts with cytosolic component(s) and impairs the assembly of NADPH oxidase.
Cell-Free System↗
B cells are generated throughout life in humans.
This analysis of B cell development as a function of age reveals a relatively widespread distribution of progenitor B (pro-B), pre-B, and B cells in fetal tissues, and thus supports the idea of a multifocal origin of B lineage cells during embryonic development. From mid-gestation onward, the bone marrow is the major site of B cell generation in humans. A relatively constant ratio of bone marrow precursors to B cells of immature phenotype (CD24highCD10+CD20lowIgD-) is maintained from mid-gestation through the eighth decade of life. The persistence of recombinase gene activity in pro-B cells further attests the sustained production of B cells in bone marrow. Interestingly, a subpopulation of B cells with mature phenotype (CD24lowCD10-CD20highIgD+) accumulates in the bone marrow during childhood, and this becomes the predominant B cell subpopulation in adult bone marrow. This mature population of bone marrow B cells may represent a subpopulation of recirculating B cells that have undergone selection in the periphery.
Adult↗
Fibronectin promotes the proliferation of cytotoxic T lymphocytes generated from cancer patients.
We studied whether fibronectin (FN) enhances the activity of autologous tumour-reactive cytotoxic T lymphocytes (CTLs) generated from cancer patients. The proliferation of CTLs stimulated by immobilised anti-CD3 monoclonal antibody and interleukin 2 (IL-2) was enhanced three or four times by immobilised FN. whereas soluble FN did not alter the DNA synthesis of CTLs. Moreover, the cytotoxic activity of CTLs was augmented by FN stimulation against autologous tumour cells [4 h 51Cr release assay: FN(+) 16.7 +/- 4.7% vs FN (-) 11.8 +/- 3.1%; 16 h 51Cr release assay: FN(+) 24.8 +/- 4.7% vs FN (-) 16.5 +/- 5.7%, P<0.05]. The major cell surface phenotype of CTLs with FN was CD3+, CD4+ and CD25+ in 6 weeks' culture. Cytotoxicity against autologous tumour cells was inhibited by anti-HLA class I monoclonal antibody (MAb). The autologous tumour-killing activity of CTLs was suppressed by the elimination of CD4+ cells. Moreover, the cytokine production of CTLs was augmented by FN stimulation. Especially, the production of IL-2, interferon gamma (IFN-gamma), and granulocyte macrophage colony-stimulating factor (GM-CSF) was significantly augmented by FN stimulation (P<0.05). Thus, CTLs generated by FN might have both killer and helper functions, since they could lyse autologous tumour cells and secrete various cytokines, including IL-2.
Adult↗
Fas antigen/APO-1 (CD95) expression on myeloma cells.
Many factors involved in the proliferation of myelomas have been reported, and the relationship between these factors and the pathogenesis of multiple myeloma has been discussed. We found that most myeloma cells express Fas antigen/APO-1 (CD95), a cell surface antigen that mediates apoptosis. However only some cells are sensitive to anti-Fas antibody and undergo apoptosis. These data indicate that some multiple myelomas are generated not only by cell proliferation but also by cell immortalization. The mechanism by which myelomas are immortalized is still unclear, but Bcl-2, Bcl-xL, adult T cell leukemia derived factor (ADF), soluble Fas are all candidate factors for this mechanism. The possibility also exists that inducers of apoptosis, e.g. tumor necrosis factor(TNF), interleukin-1 beta-converting enzyme(ICE), Bcl-xS, or Bax, do not have a lethal effect. In this review, we focus on the system that immortalizes myeloma cells, and suggest the possibility that multiple myeloma constitutes one group of cells which cannot undergo apoptosis in the bone marrow.
Apoptosis↗
Myeloma cells express Fas antigen/APO-1 (CD95) but only some are sensitive to anti-Fas antibody resulting in apoptosis.
To find out which cytokines are involved in the pathogenesis of multiple myeloma, we investigated cytokine receptor expression on myeloma cells using a panel of monoclonal antibodies (MoAbs). Flow cytometric analysis of five myeloma cell lines (RPMI8226, ARH77, KMM-1, U266, and Hs) and myeloma cells freshly isolated from eight patients showed that interleukin-1 receptor (IL-1R) type I and type II, IL-2R alpha and beta chains, IL-4R, IL-6R, IL-7R, IL-8R, granulocyte macrophage colony-stimulating factor receptor (GM-CSFR), c-kit (stem cell factor receptor [SCFR]), membrane bound stem cell factor (MBSCF), and tumor necrosis factor (TNF) receptors type I and type II were not always detected on the myeloma cells. However, interferon-gamma receptor, gp130, and Fas antigen were constitutively expressed, except one sample. To determine the role of Fas antigen on myeloma cells, these cells were cultured with anti-Fas MoAb. Apoptotic changes characterized by loss of cell volume, membrane blebbing, fragmentation of nuclei, and condensed chromatin were observed in three of five myeloma cell lines. When bcl-2 expression was examined, it was seen in all the cell lines regardless of the sensitivity to anti-Fas MoAb. Furthermore, anti-Fas MoAb not only induced apoptosis of freshly isolated myeloma cells but also inhibited the DNA synthesis, although such effects varied from patient to patient. The data indicate that only some myeloma cells undergo apoptosis in response to the signal mediated by the Fas antigen.
Adult↗
Serum interleukin 6 as a predicator of the therapeutic effect and adverse reactions after transcatheter arterial embolization.
To evaluate the value of serum interleukin 6 (sIL-6) for the prediction of therapeutic effect and adverse reaction after transcatheter arterial embolization (TAE), sIL-6 was measured before and after angiography or TAE in 18 patients (three after angiography and 15 after TAE for hepatocellular carcinoma). The three patients with only angiography showed no elevation of sIL-6, while a significant increase was observed after TAE in the 15 hepatocellular carcinoma patients. The sIL-6 levels of patients with a partial response to TAE were higher at 48-72 hours after the procedure than those of patients with no response (P = 0.045), and the sIL-6 levels of patients who showed adverse reactions were higher at 6-24 h than those of patients without adverse reactions (P = 0.019). sIL-6 level at 48-72 h after TAE reflects the efficacy of TAE, whereas the level at 6-24 h after TAE is related to the severity of adverse reactions. Therefore, sIL-6 may be a useful indicator for prediction of the therapeutic effect of TAE as well as adverse reactions.
Aged↗
Gp130 in human myeloma/plasmacytoma.
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Antibodies, Monoclonal↗
Transfer of rheumatoid arthritis into severe combined immunodeficient mice. The pathogenetic implications of T cell populations oligoclonally expanding in the rheumatoid joints.
To investigate the pathogenicity of T cells infiltrating in the rheumatoid joints, mononuclear cells (MNC), predominantly T cells, isolated from either synovial fluid or synovial tissues of the patients with RA were transferred into severe combined immunodeficient (SCID) mice by intraarticular injections. According to our observations in this experimental system, patients with RA could be classified into at least two groups. In one group of patients, the infiltrating MNC induced synovial hyperplasia in the recipient SCID mice (the positive group). Whereas, in the other group no synovial hyperplasia was observed (the negative group). The induction of synovial hyperplasia observed in the positive group was prevented by an anti-human CD3 antibody (OKT3), indicating T cell mediation. Analysis of T cell receptor (TCR) V beta usage by reverse transcriptase polymerase chain reaction in the infiltrating MNC transferred into SCID mice revealed a marked skew towards the preferential use of certain V beta genes, which was not seen in the peripheral blood MNC, in only the positive group. The patterns of TCR/V beta skew were not uniform among the patients. The analysis of the PCR-amplified genes of such skewed TCR/ V beta by single strand conformational polymorphism showed distinct bands, indicating that the T cell populations expanding in rheumatoid joints of the positive group were oligoclonal. Furthermore, the enrichment of the T cell populations expressing such skewed TCR/V beta by in vitro stimulation of peripheral blood MNC of the patients with the relevant superantigen enabled the induction of synovial hyperplasia in the SCID mice. These results suggest that the pathogenic T cells could be activated locally in rheumatoid joints by certain antigens in some, but not in all patients with RA.
Animals↗
[Enzyme immunoassay for cytokines].
Cytokines produced by different types of cells function by cell to cell interaction both in vitro and in vivo. Over thirty different molecules react in almost all physiological phenomena, such as in the fields of immunology, hematology, endocrinology, neurology, cardiology and nephrology. Previous observations indicate that the abnormal production of cytokines plays a part of pathogenesis of diseases. Therefore, it is necessary to know the amount of cytokines in the biological specimens for recognizing the pathogenic significance of cytokines. In this paper, we show the EIA-Kits of cytokines which are purchased. And we demonstrate the methods, advantages and disadvantages in the different enzyme immunoassays (EIA, DELFIA and Chemiluminescen-EIA) of interleukin 6 which we extensively investigated from basic to clinical experiments may be routinely used in the clinical examination in the near future.
Biomarkers↗
Inhibitory effect of all-trans retinoic acid on the growth of freshly isolated myeloma cells via interference with interleukin-6 signal transduction.
We showed the dose-dependent growth inhibition by alltrans retinoic acid (ATRA) of myeloma cells freshly isolated from patients. ATRA downregulated the cell surface expression of interleukin-6 receptor (IL-6R) and/or glycoprotein (gp) 130. The growth-inhibitory activity of ATRA was well correlated with that of anti-gp 130 antibody in every sample. Furthermore, ATRA inhibited the production of IL-6 from both myeloma cells and marrow stromal cells, and recombinant IL-6 (rIL-6) could partially recover the myeloma cell growth that had been inhibited by ATRA. These data suggest that ATRA may inhibit the proliferation of myeloma cells both by the downregulation of IL-6R and gp130 expression on myeloma cells and by the inhibition of IL-6 production from myeloma and stromal cells. Prednisolone (PSL) and interferon-gamma (IFN-gamma) also inhibited the myeloma growth, while their effects were different from those of ATRA on IL-6 R and gp130 expression, IL-6 production, and morphological change. The inhibitory effect of ATRA on myeloma cell proliferation was observed in 10 of 14 samples obtained from eight patients, which suggests that ATRA may be a potent new therapeutic agent for some myeloma patients.
Antigens, CD↗
Oncostatin M, leukemia inhibitory factor, and interleukin 6 induce the proliferation of human plasmacytoma cells via the common signal transducer, gp130.
We analyzed the stimulatory effect of oncostatin M (OSM), leukemia inhibitory factor (LIF), interleukin 6 (IL-6), IL-11, and the inhibitory effect of anti-IL-6 antibody (Ab), anti-IL-6 receptor monoclonal antibody (mAb), and anti-gp130 mAb on the growth of human plasmacytoma cells freshly isolated from a patient with multiple myeloma. The purified cells showed a plasmacytoid morphology and expressed CD38, CD54, and CD56 antigens but no CD3, CD5, CD10, CD19, CD20, or very late antigen 5. IL-6 receptor (IL-6R) and its signal transducer, gp130, were expressed on their cell surface at a low level. Dose-dependent proliferation of the cells in response to OSM, LIF, and IL-6, but not to IL-11, was observed using [3H]TdR incorporation in vitro. Both anti-IL-6 Ab and anti-IL-6R mAb inhibited the growth of the cells in the presence or absence of exogenous IL-6. These cells release IL-6 but not OSM or LIF into the culture supernatant during short-term culture. Therefore, an autocrine growth mechanism mediated by IL-6, but not by OSM or LIF, was confirmed. Furthermore, anti-gp130 mAb completely inhibited the proliferation of the cells induced by OSM, LIF, as well as IL-6. These data indicate that OSM, LIF, and IL-6 can act as growth factors of human plasmacytoma cells through a common signal transducer, gp130, on their cell surface, and also suggest the potential therapeutic application of anti-gp130 mAb, as well as anti-IL-6R mAb against myeloma/plasmacytomas.
Antibodies, Monoclonal↗
[Case of thrombotic thrombocytopenic purpura treated with plasma exchange and immunoglobulin therapy].
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Adolescent↗
[Interleukin-6].
Interleukin-6 (IL-6) was found to be a pleiotropic cytokine which plays important roles not only in immune response but also in inflammation and hematopoiesis since the cDNA for IL-6 was originally cloned as a B cell differentiation factor (BCDF). IL-11, leukemia inhibitory factor, oncostatin M, and ciliary neurotrophic factor have similar effects with IL-6. This functional redundancy was well explained by the common signal transducer gp 130. Furthermore, recent studies have revealed the mechanisms to regulate the gene expression of IL-6 and to transduce the signal through IL-6 receptor system. On the basis of these results, elucidation of pathogenic significances of IL-6 and new therapeutic approaches in various diseases are now expected.
Animals↗
Systemic production of interleukin-6 following acute inflammation.
The present study was designed to evaluate whether IL-6 is produced locally or systemically following acute inflammation. Full-thickness scale burns were made on rats. Serum IL-6 levels (SIL-6) showed a constant time-dependent change with a single peak 6 hours after the burn. SIL-6 elevation was correlated with the ratio of burn area to total body surface area. The liver, spleen, lymph node and skin harvested after the burn secreted significantly higher amounts of IL-6 after tissue culture when compared with those taken from sham rats. The venous serum drainage from the burn site induced significantly higher IL-6 production of splenocytes than the arterial and control venous sera. In conclusion, IL-6 production is rapidly and systemically triggered by a humoral factor following acute inflammation in vivo, resulting in constant kinetics for SIL-6.
Animals↗
Serum interleukin-6 levels as an indicator of acute rejection after liver transplantation in cynomologous monkeys.
This study was designed to evaluate whether the sequential monitoring of serum interleukin-6 levels (SIL-6) could be helpful for diagnosing the occurrence of hepatic allograft rejection. An SIL-6 post-transplant study was conducted on nine cynomolgus monkeys which had undergone orthotopic hepatic allotransplantation, six of which were treated with FK-506 (a new immunosuppressant agent isolated from Streptomyces tsukubaensis) and three of which were not. All the nontreated animals showed biochemical abnormalities from days 5-6, characterized by a marked elevation of serum alkaline phosphatase levels, and they eventually died on days 8, 12, and 63 (group I). Acute cellular rejection was confirmed by histological study of the hepatic grafts taken at autopsy or biopsy. On the other hand, four of the treated animals (group IIa) survived more than 30 days. Biochemical examination of this group showed no abnormal signs apart from a slight elevation of alkaline phosphatase (< 2000 IU/l). Histological examination carried out around 30 days after transplantation revealed a transient infiltration of polynuclear cells into Glisson's area, with the portal vein and bile duct remaining intact. The remaining two animals (group IIb) died of dehydration and arterial thrombosis on days 5 and 7, respectively. A kinetic study of SIL-6 conducted during the first 2 weeks showed quite different patterns among the three groups. All recipients in group I demonstrated two peaks following grafting on days 1 and 3 or 4, the second peak of above 2.0 U/ml preceding biochemical abnormalities by 2 to 3 days.(ABSTRACT TRUNCATED AT 250 WORDS)
Alkaline Phosphatase↗
Regulation of hepatic lipogenic enzyme gene expression by diet quantity in rats fed a fat-free, high carbohydrate diet.
This investigation concerns the effects of the level of intake of a high carbohydrate diet on transcriptional rate, mRNA concentration and enzyme induction for lipogenic enzymes in rat liver. Six hours after refeeding fasted rats, the transcriptional rates in livers reached low maximum levels with small quantities of diet, but the mRNA concentrations continued to increase as diet intake increased. Greater diet intake primarily increased transcriptional rates and mRNA concentrations of lipogenic enzymes. After refeeding for 16 h, the mRNA concentrations were sigmoidly increased relative to the diet quantity and reached maximum levels of 20-, 110-, 22- and 16-fold above each fasted level for acetyl-CoA carboxylase, fatty acid synthase, malic enzyme and glucose-6-phosphate dehydrogenase, respectively. After 3 d of refeeding (in a steady state of lipogenic enzyme activities), however, the transcriptional rates, mRNA concentrations and activity inductions of all the enzymes were sigmoidly increased relative to diet quantity, but were not different among the enzymes. Consequently, fatty acid synthesis and triglyceride levels in the liver were not increased by feeding less than 70% of ad libitum intake but were greatly increased by feeding greater than 70% of ad libitum intake.
Acetyl-CoA Carboxylase↗
Interleukin-6 as a new indicator of inflammatory status: detection of serum levels of interleukin-6 and C-reactive protein after surgery.
Postoperative serum interleukin-6 (SIL-6) and C-reactive protein (SCRP) levels were examined in 71 patients who underwent various types of abdominal surgery. Similar time-dependent changes in SIL-6 and SCRP levels were observed in 12 patients despite differences in surgical procedures and liver function among the patients. SIL-6 started to increase within 3 hours after the beginning of the operation and reached a peak after 24 hours. SCRP started to increase after 12 hours and was maximum at 48 to 72 hours. The increase in SIL-6 at 24 hours (delta IL-6) showed a close correlation with that of SCRP at 48 hours (delta CRP) in 53 patients without liver cirrhosis. In 18 patients with liver cirrhosis, delta CRP relative to delta IL-6 was less than that in patients without cirrhosis and was poorly correlated with the latter. delta IL-6 was correlated with the length of time of the operation and blood loss in both groups, but delta CRP showed no significant correlation with these factors in either group. These findings indicate that the increase in IL-6 triggered by a surgical procedure may function as a hepatocyte-stimulating factor and that monitoring of SIL-6 may be more helpful than monitoring of SCRP for estimation of inflammatory status and early detection of an acute-phase response.
Abdomen↗