Search PubMed⌕ Search

Biomedical subjects

N Yamauchi

Publications and source records attributed to N Yamauchi.

At least 19 recordsLinked to original sources
PubMed2000

Constitutive tyrosine phosphorylation of ErbB-2 via Jak2 by autocrine secretion of prolactin in human breast cancer.

Overexpression of the oncogene for ErbB-2 is an unfavorable prognostic marker in human breast cancer. Its oncogenic potential appears to depend on the state of tyrosine phosphorylation. However, the mechanisms by which ErbB-2 is constitutively tyrosine-phosphorylated in human breast cancer are poorly understood. We now show that human breast carcinoma samples with ErbB-2 overexpression have higher proliferative and metastatic activity in the presence of autocrine secretion of prolactin (PRL). By using a neutralizing antibody or dominant negative (DN) strategies or specific inhibitors, we also show that activation of Janus kinase Jak2 by autocrine secretion of PRL is one of the significant components of constitutive tyrosine phosphorylation of ErbB-2, its association with Grb2 and activation of mitogen-activated protein (MAP) kinase in human breast cancer cell lines that overexpress ErbB-2. Furthermore, the neutralizing anti-PRL antibody or erbB-2 antisense oligonucleotide or DN Jak2 or Jak2 inhibitor or DNRas or MAP kinase kinase inhibitor inhibits the proliferation of both untreated and PRL-treated cells. Our results indicate that autocrine secretion of PRL stimulates tyrosine phosphorylation of ErbB-2 by Jak2, provides docking sites for Grb2 and stimulates Ras-MAP kinase cascade, thereby causing unrestricted cellular proliferation. The identification of this novel cross-talk between ErbB-2 and the autocrine growth stimulatory loop for PRL may provide new targets for therapeutic and preventive intervention of human breast cancer.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Effects of sodium pyruvate in nonserum maturation medium on maturation, fertilization, and subsequent development of bovine oocytes with or without cumulus cells.

The present study was conducted to determine the effects of cumulus cells and sodium pyruvate during in vitro maturation of bovine oocytes on maturation, fertilization, and subsequent development. Cumulus-enclosed oocytes (CEOs) and cumulus-denuded oocytes (CDOs) were cultured for 24 h in polyvinylpyrrolidone-Hepes-tissue culture medium 199 with or without sodium pyruvate. Oocytes were fertilized in vitro and then cultured in CR1aa for 10 days. Before in vitro fertilization, the glutathione (GSH) content of some oocytes was measured. Maturation and normal fertilization rates of CDOs cultured with sodium pyruvate and CEOs were higher than that of CDOs cultured without sodium pyruvate. The CEOs showed significantly higher rates of development to the blastocyst stage than CDOs. The GSH contents of oocytes significantly decreased in CDOs after maturation culture, but the GSH contents of oocytes in CEOs remained at the same level as oocytes before culture. These results indicate that sodium pyruvate promotes nuclear maturation of bovine CDOs and that a continuing presence of cumulus cells during maturation is important for subsequent development of zygotes to the blastocyst stage. However, blastocysts produced from CDOs in the presence of sodium pyruvate showed a developmental competence to be normal calves, but it is not known if CDOs cultured without sodium pyruvate also were capable of developing into calves.

Animals↗
PubMed2000

In vivo gene delivery to tumor cells by transferrin-streptavidin-DNA conjugate.

To target disseminated tumors in vivo, transgenes [beta-galactosidase gene, green fluorescence protein (GFP) gene, herpes simplex virus thymidine kinase (HSV-TK)] were conjugated to transferrin (Tf) by a biotin-streptavidin bridging, which is stoichiometrically controllable, and Tf receptor (Tf-R) affinity chromatography, which selects Tf conjugates with intact receptor bindings sites from reacting with the linker. Tf-beta-galactosidase plasmid conjugate thus constructed was specifically transfected to human erythroleukemia cells (K562) via Tf-R without the aid of any lysosomotropic agents. The transfection efficiency of the conjugate was superior to those of lipofection (1% staining) and retroviral vector (5%) and slightly lower than that of adenovirus (70%). The high level of expression with our conjugate was confirmed using other tumor cells (M7609, TMK-1) whereas in normal diploid cells (HEL), which express low levels of Tf-R, expression was negligible. When GFP gene conjugates were systemically administered through the tail vein to nude mice subcutaneously inoculated with tumor, expression of GFP mRNA was found almost exclusively in tumors and to a much lesser extent in muscles, whereas GFP revealed by fluorescence microscopy was detected only in the former. To exploit a therapeutic applicability of this method, suicide gene therapy using Tf-HSV-TK gene conjugate for massively metastasized k562 tumors in severe combined immune-deficient mice was conducted, and a marked prolongation of survival and significant reduction of tumor burden were confirmed. Thus, this method could also be used for gene therapy to disseminated tumors.

Animals↗
PubMed2000

Synergistic suppressive effect of double transfection of tumor necrosis factor-alpha and interleukin 12 genes on tumorigenicity of Meth-A cells.

Tumor necrosis factor-alpha (TNF-alpha) and interleukin 12 (IL-12), both potent antitumor cytokines, are known to be involved in the host's antitumor immune surveillance in tumor bearers, via different mechanisms. The former enhances the activities of dendritic cells, natural killer / lymphocyte-activated killer (NK / LAK) and cytotoxic T lymphocyte (CTL), while the latter induces Th1-type cellular immunity and enhances the activities of natural killer T (NKT), NK / LAK and CTL. In the present study, in the expectation of synergistic actions of these cytokines in stimulating the host's immune responses, we investigated the feasibility of a cancer vaccine involving double transfection with both genes in a murine model. The expression of major histocompatibility complex (MHC) class I, class II and B7.1 on the surface of the double transfectants was enhanced as revealed by FACS analysis. A significant decrease in tumorigenicity was observed in mice inoculated with the double transfectants. Cytotoxicity assay revealed that the activities of NK / LAK and CTL from spleens of mice bearing the double transfectants were enhanced. The induction of tumor-specific immunity was confirmed by rechallenge with parental Meth-A cells in mice that had rejected the double transfectants. Thus, double transfection of TNF-alpha and IL-12 genes was considered to bring about synergistic suppressive effects on the tumorigenicity of transfectants through the activation of killer cells by produced cytokines and the enhancement of expression of MHC class I, II and B7.1 molecules.

Adenocarcinoma↗
PubMed2000

Autoantibodies against the specific epitope of human tropomyosin(s) detected by a peptide based enzyme immunoassay in sera of patients with ulcerative colitis show antibody dependent cell mediated cytotoxicity against HLA-DPw9 transfected L cells.

BACKGROUND AND AIMS: Recent studies suggest that tropomyosin (TM) may act as a putative autoantigen in ulcerative colitis (UC). Recently, we identified, by computer homology analysis, a specific peptide (HIAEDADRK) in human TM that can bind to HLA-DPw9. The aim of this study was to investigate the presence of autoantibodies against this peptide in UC. METHODS: Antibodies were measured by ELISA with a synthetic peptide in 20 healthy volunteers, 48 patients with UC, 26 with Crohn's disease (CD), eight with primary sclerosing cholangitis (PSC), and six with primary biliary cirrhosis (PBC). The functional significance of antibodies was investigated by antibody dependent cell mediated cytotoxicity (ADCC) against DPw9 transfected L cells using a standard (51)Cr release assay. RESULTS: Optical density values (mean (SD)) of sera from patients with UC (1.40 (0. 52)) and PSC (1.65 (0.12)) were significantly higher than those from healthy volunteers (0.32 (0.28)) (p<0.05), CD (0.50 (0.34)) (p<0.05) and PBC (0.14 (0.09)) (p<0.05). Values in UC decreased with clinical improvement. The ADCC activity of UC sera correlated well with antibody titre against this synthetic peptide. CONCLUSIONS: Anti-TM antibody was detected in UC sera by a specific peptide based ELISA with high reproducibility. This peptide may be an antigenic epitope of TM involved in the immunopathogenesis of UC and, perhaps, PSC.

Adolescent↗
PubMed2000

The association of calprotectin level in gingival crevicular fluid with gingival index and the activities of collagenase and aspartate aminotransferase in adult periodontitis patients.

BACKGROUND: Calprotectin, a major cytosol protein of leukocytes, exists in plasma and other body fluids of healthy human subjects. Since the calprotectin concentration rises markedly in some inflammatory diseases including rheumatoid arthritis, this protein has been thought to be a marker of inflammatory disease. Recently, we identified calprotectin in human dental calculus and gingival crevicular fluid (GCF), and found that the calprotectin concentration in GCF from patients with periodontitis was significantly higher than that in GCF from healthy subjects. In the present study, the association of GCF calprotectin level with GCF volume, gingival index (GI), and levels of biochemical markers including collagenase and aspartate aminotransferase (AST) in GCF was investigated to clarify the relationship between GCF calprotectin level and periodontal inflammation. METHODS: Ninety GCF samples collected from periodontal pockets with a probing depth of more than 4 mm in 54 patients with adult periodontitis were used for these assays. The GCF volume was measured, and GI in each site was recorded. The calprotectin content in GCF samples was determined by ELISA using a specific antibody. The activity of collagenase or AST was measured by a respective assay kit. RESULTS: The total amount of calprotectin and GCF volume showed a highly significant correlation (r = 0.64, P <0.0001), whereas the calprotectin concentration had no correlation with the GCF volume (r = 0.01, P= 0.924). The mean calprotectin concentration in GCF increased with the degree of GI, and the concentration in individual samples was significantly correlated with the GI score (r = 0.56, P<0.0001). Significant positive correlations were observed in GCF calprotectin versus collagenase (r = 0.57, P <0.0001) and GCF calprotectin versus AST levels (r = 0.40, P <0.005). CONCLUSIONS: From the present results and our previous findings, it is shown that the GCF calprotectin level significantly correlates not only with clinical indicators but also with current biochemical marker levels and that calprotectin may be a useful marker for periodontal inflammation.

Adult↗
PubMed1999

Psychological stress increased corticotropin-releasing hormone mRNA and content in the central nucleus of the amygdala but not in the hypothalamic paraventricular nucleus in the rat.

The central administration of corticotropin-releasing hormone (CRH) to experimental animals sets into motion a coordinated series of physiological and behavioral events that promote survival during threatening situation. A large body of evidence suggest that CRH in the central nucleus of the amygdala (CEA) induces fear-related behaviors and is essential to fear conditioning; however, evidence of CRH-mediated activation of the amygdala under physiological situation is still limited. We report here a study of the impact of a psychological stressor on hypothalamic and amygdala CRH systems in the rat. Non-footshocked rats placed in a floored compartment surrounded by footshocked rats were defined as the psychological stress group. Rats were exposed to psychological stress for 15 min, and then sacrificed 1.5 and 3 h after cessation of stress. We found that our psychological stressor induced an increase in both CRH mRNA levels, as assessed by in situ hybridization histochemistry, and CRH content, as assessed by micropunch RIA, in the CEA. Exposure to the psychological stressor also caused a significant increase in CRH mRNA levels with a trend for an increase in CRH content in the dorsolateral subdivision of the bed nucleus of the stria terminalis (BNST) which is anatomically associated with the CEA. In contrast, psychological stress induced a small, but significant increase in type-1 CRH receptor (CRHR-1) mRNA in the hypothalamic paraventricular nucleus (PVN), while it failed to elevate either PVN CRH mRNA levels or content, CRH content in the median eminence (ME), or levels of plasma ACTH or corticosterone (CORT). Thus, in the context of a psychological stressor, the activation of the amygdala CRH system can occur without robust activation of the hypothalamic CRH system. In the light of previous data that the psychological stress-induced loss of sleep was reversed by the central administration of a CRH antagonist, these data suggest that CRH in the CEA may contribute to the psychological stress-evoked fear-related behavior such as hyperarousal. These data also indicate that in response to a psychological stressor, the amygdala CRH system is much more sensitive than is the CRH system emanating from the PVN.

Adrenocorticotropic Hormone↗
PubMed1999

Effects of hormones and osmolarity in the culture medium on germinal vesicle breakdown of porcine oocytes.

The present study was conducted to examine effects of hormones and osmolarity on germinal vesicle breakdown (GVBD) and histone H1 kinase (H1K) activity in porcine oocytes cultured in vitro. The basic medium used for culture of oocytes was modified Tyrode's solution in which the osmolarity was adjusted to 134 to 495 mOsm by changing the concentration of sodium chloride (NaCl). When the hormones were present, osmolarity of medium that allows GVBD of oocytes was less than 400 mOsm. However, the range of osmolarity of medium that allows meiotic maturation of oocytes was 210 to 362 mOsm. On the other hand, without hormonal supplement, the incidence of GVBD in oocytes decreased as the osmolarity of the medium increased in the rage of 210 to 362 mOsm. By increasing the osmolarity of the medium from 210 to 362 mOsm by addition with sorbitol instead of NaCl, the incidence decreased from 89.1% to 13.3%. In oocytes cultured in medium of 210 mOsm without hormones, the percentage of oocytes that underwent GVBD and had increased H1K activity 20 h after culture was significantly higher (P < 0.05) than those of oocytes cultured in the same medium supplemented with hormones or medium of 362 mOsm. These results indicate that in vitro induction of GVBD in porcine oocytes is strongly affected by osmolarity of the medium in the absence of hormones. The results also suggest that, under low osmolarity (210 mOsm), GVBD is accelerated with rapid increase of H1K activity.

Animals↗
PubMed1999

Role of NADH shuttle system in glucose-induced activation of mitochondrial metabolism and insulin secretion.

Glucose metabolism in glycolysis and in mitochondria is pivotal to glucose-induced insulin secretion from pancreatic beta cells. One or more factors derived from glycolysis other than pyruvate appear to be required for the generation of mitochondrial signals that lead to insulin secretion. The electrons of the glycolysis-derived reduced form of nicotinamide adenine dinucleotide (NADH) are transferred to mitochondria through the NADH shuttle system. By abolishing the NADH shuttle function, glucose-induced increases in NADH autofluorescence, mitochondrial membrane potential, and adenosine triphosphate content were reduced and glucose-induced insulin secretion was abrogated. The NADH shuttle evidently couples glycolysis with activation of mitochondrial energy metabolism to trigger insulin secretion.

Adenosine Triphosphate↗
PubMed1999

Stimulatory effects of phenytoin on osteoblastic differentiation of fetal rat calvaria cells in culture.

Phenytoin (diphenylhydantoin, DPH), an anticonvulsant drug for epileptic patients, has several adverse effects, including calvarial thickening and coarsening of the facial features, which occur with chronic DPH therapy. While previous studies have demonstrated that DPH has an anabolic action on bone cells in vivo and in vitro, the basis of these effects is not fully understood. In this study, the effect of DPH on osteoblastic differentiation of fetal rat calvaria (RC) cells in culture was investigated by measuring bone nodule (BN) formation, cell growth, alkaline phosphatase (ALPase) activity, collagen synthesis, and expression of osteocalcin (OC) and osteopontin (OP) mRNAs. Continuous treatment of RC cells with DPH for 18 days dose-dependently increased the mineralized BN number by 1.2-1.7-fold at concentrations of 12.5-200 micromol/L DPH. Cell growth was not affected at the same concentrations of DPH. ALPase activity was stimulated by DPH (1.1-1.9-fold) dose-dependently and was maintained at higher levels in DPH-treated cells throughout the experimental period. DPH increased mineralized and unmineralized BN formations both in the presence and the absence of 10(-8) mol/L dexamethasone (Dex). Expression of OC and OP mRNAs was markedly augmented by DPH on days 12-24 and on days 12-18, respectively. While control mRNA levels of OC and OP increased with time, the increases in DPH-treated cells were greater than those of the controls and the stimulatory effects were dose-dependent. Type I collagen was also influenced by DPH; mRNA level was enhanced and the percentage of collagen synthesized was increased significantly, by 200 micromol/L DPH. When DPH was added in three different culture stages, days 1-6 (growth), days 7-12 (matrix development), and days 13-18 (mineralization), BN formation was influenced primarily on days 1-6 and secondarily on days 7-12, but not on days 13-18, suggesting that DPH increased BN formation by enhancing not only the proportion of osteoprogenitor cells in the early stage but also the proportion of functional osteoblasts in the middle stage within mixed-cell populations. Moreover, such increases were detected in conditions of both Dex(+) and Dex(-). These findings demonstrate that DPH stimulates osteoblast-associated markers such as BNs, ALPase, OC, OP, and type I collagen by continuously affecting the stages of growth and matrix development in RC cells, and suggests that the stimulatory effects by DPH may possibly be induced independent of those by Dex.

Alkaline Phosphatase↗
PubMed1999

Calprotectin in gingival crevicular fluid correlates with clinical and biochemical markers of periodontal disease.

Clinical and biochemical markers of periodontal disease have been used for precise objective diagnosis of periodontal inflammation. Interleukin 1beta (IL-1beta) and prostaglandin E2 (PGE2), inflammatory factors, levels in gingival crevicular fluid (GCF) of patients with periodontal disease are elevated and have been studied as biochemical markers. The levels of calprotectin, a leukocyte protein, in body fluids of patients with some inflammatory diseases are raised. Recently, we detected calprotectin in GCF and its concentrations in periodontal pockets were higher than those in healthy gingival crevices. In this study, we investigated the correlations between GCF calprotectin levels and clinical indicators (probing depth and bleeding on probing, BOP), and the IL-1beta or PGE2 levels in GCE Probing depth and BOP at 130 sites of 110 subjects with periodontal or other oral diseases were examined, then GCF samples were collected and their calprotectin, IL-1beta and PGE2 were determined by ELISA. The calprotectin level correlated positively with the probing depth and was significantly higher at BOP-positive than BOP-negative sites. There were significant, positive correlations between the calprotectin and IL-1beta or PGE2 concentrations. These results indicate that the calprotectin level in GCF correlates well with clinical and biochemical markers of periodontal disease and suggest that calprotectin may be useful for evaluating the extent of periodontal inflammation.

Adult↗
PubMed1999

Male pronuclear formation in denuded porcine oocytes after in vitro maturation in the presence of cysteamine.

The present study was conducted to examine effects of cysteamine in culture medium on progression of meiosis, glutathione (GSH) content, kinase activities (histone H1 kinase and mitogen-activated protein kinase), and male pronuclear formation after in vitro insemination of cumulus-denuded oocytes (DOs) in the pig. DOs, obtained by mechanically removing cells from cumulus-oocyte complexes (COCs) with a small-bore pipette, were cultured for 45 h in TCM199 supplemented with sodium pyruvate, gonadotropins, estradiol, and 10% porcine follicular fluid, with or without cysteamine (150 microM). Maturation rates of DOs cultured with and without cysteamine were not different (60-70%) but were significantly lower than those of COCs (90-100%) (p < 0.05). GSH content of matured DOs cultured with cysteamine was significantly higher than that of DOs cultured without cysteamine (p < 0.05). Values for both types of kinase activity in matured DOs cultured with and without cysteamine were not different (p > 0.05). After in vitro insemination, DOs cultured with cysteamine showed significantly higher rates of male pronuclear formation (80.3 +/- 3.0%) than DOs cultured without cysteamine (16.4 +/- 0.5%) (p < 0.05). These results indicate that the addition of cysteamine to culture medium increased oocyte GSH content and promoted male pronuclear formation after sperm penetration of porcine DOs but had no effects on their maturation rates or kinase activities.

Animals↗
PubMed1999

Inhibition of osteoblastic cell differentiation by lipopolysaccharide extract from Porphyromonas gingivalis.

Lipopolysaccharide from Porphyromonas gingivalis (P-LPS), an important pathogenic bacterium, is closely associated with inflammatory destruction of periodontal tissues. P-LPS induces the release of cytokines and local factors from inflammatory cells, stimulates osteoclastic-cell differentiation, and causes alveolar bone resorption. However, the effect of P-LPS on osteoblastic-cell differentiation remains unclear. In this study, we investigated the effect of P-LPS extract prepared by the hot-phenol-water method, on the differentiation of primary fetal rat calvaria (RC) cells, which contain a subpopulation of osteoprogenitor cells, into osteoblastic cells. P-LPS extract significantly inhibited bone nodule (BN) formation and the activity of alkaline phosphatase (ALPase), an osteoblastic marker, in a dose-dependent manner (0 to 100 ng of P-LPS extract per ml). P-LPS extract (100 ng/ml) significantly decreased BN formation to 27% of the control value and inhibited ALPase activity to approximately 60% of the control level on days 10 to 21 but did not affect RC cell proliferation and viability. P-LPS extract time-dependently suppressed the expression of ALPase mRNA, with an inhibitory pattern similar to that of enzyme activity. The expression of mRNAs for osteocalcin and osteopontin, matrix proteins related to bone metabolism, was markedly suppressed by P-LPS extract. Furthermore, P-LPS extract increased the expression of mRNAs for CD14, LPS receptor, and interleukin-1beta in RC cells. These results indicate that P-LPS inhibits osteoblastic-cell differentiation and suggest that LPS-induced bone resorption in periodontal disease may be mediated by effects on osteoblastic as well as osteoclastic cells.

Alkaline Phosphatase↗
PubMed1999

Cytoplasmic maturation for activation of pig follicular oocytes cultured and arrested at metaphase I.

A large population (62-90%) of pig follicular oocytes can mature to metaphase II after culture for 48 h. However, a proportion (6-22%) remain in an immature stage at metaphase I (metaphase I-arrested). The main objective of this study was to determine whether the cytoplasm of metaphase I-arrested pig oocytes is capable of being activated by sperm penetration or parthenogenetic stimulation. After culture for 48 h, oocytes without a polar body (73% were shown to be at metaphase I after staining) and those with a polar body (94% were at metaphase II) were fertilized in vitro. A total of 69% and 62% of the oocytes were activated to form a female pronucleus, respectively, and the rate of polar body extrusion induced by fertilization in the activated oocytes was 90% (the first polar body) and 95% (the second polar body), respectively. When oocytes without and with a polar body were stimulated with an electric pulse, 53% and 81% of the oocytes were activated, respectively. The rate of polar body extrusion in the activated oocytes was 73% (the first polar body) and 79% (the second polar body), respectively. In contrast, young metaphase I oocytes cultured for 24 h had low (6%) or zero activation rate after in vitro fertilization or electric pulse stimulation. However, about one-third of the young metaphase I oocytes penetrated by spermatozoa after in vitro fertilization responded to electric pulse 12 h after insemination, and almost all (93%) were activated when they were stimulated 24 h after insemination. Patterns of polypeptide synthesis and histone H1 kinase activity were similar in metaphase I-arrested and metaphase II oocytes, and were characterized by increase in a 25 kDa polypeptide and by decrease in kinase activity. Although the first step of meiotic division is impaired, these results indicate that metaphase I-arrested oocytes are mature cytoplasmically.

Analysis of Variance↗
PubMed1999

[Waldenström macroglobulinemia with diffuse large B-cell lymphoma that developed from a different B-cell clone].

A 62-year-old man was given a diagnosis of Waldenström macroglobulinemia (WM) in January 1995. He was treated with melphalan and corticosteroid until January 1996, when he experienced high fever and weight loss. The patient visited a nearby hospital, received a diagnosis of liver abscess, and was referred to our hospital on February 23, 1996. Computed axial tomographic scans demonstrated multiple isodensity masses in the liver, left adrenal region, and right kidney hilum. Needle biopsy specimens of a liver mass revealed infiltration of diffuse large B-cell lymphoma (REAL classification), suggesting that non-Hodgkin's lymphoma supervened WM. Despite multiple cycles of chemotherapy, the lymphoma responded poorly. The patient died of pneumonia and sepsis on May 10, 1996 and an autopsy disclosed broad involvement of liver and spleen with lymphoma. Southern blot analysis of DNA samples obtained from the patient's bone marrow at the time of the initial diagnosis of WM, and later from the needle biopsy specimen of liver mass, displayed different patterns of immunoglobulin heavy chain gene rearrangement. We therefore concluded that in this patient the lymphoma was not a progression of WM, but rather, an independent B-cell malignancy.

B-Lymphocytes↗
PubMed1998

The growth hormone secretagogue KP-102-induced stimulation of food intake is modified by fasting, restraint stress, and somatostatin in rats.

The effects of fasting, restraint stress, and intracerebroventricular (i.c.v.) injection of somatostatin on the growth hormone secretagogue, KP-102-induced stimulation of food intake were examined in rats. KP-102-induced stimulation of food intake was observed in freely-fed rats but not in 24-h starved rats. A 90 min period of restraint stress decreased food intake, and i.c.v. administration of KP-102 counteracted the suppressive effect of restraint on food intake. I.c.v. administration of somatostatin partially attenuated the KP-102-induced stimulation of food intake in freely-fed rats, while somatostatin itself did not change food intake. These results suggest that the stimulatory effect of KP-102 on feeding behavior is evident in freely-fed rats but not in starved rats, and that the effect of KP-102 is counteracted or attenuated by stress or somatostatin.

Animals↗
PubMed1998

Differentiation induction by a tumor-necrosis-factor mutant 471 in human myelogenous leukemic cells via tumor-necrosis-factor receptor-p55.

The present study examined differentiation-inducing activity by various tumor-necrosis-factor(TNF) mutants against the human leukemic cell lines HL-60 and U-937. Mutant TNF 471, from which 7 N-terminal amino acids of native TNF were deleted and Pro8, Ser9 and Asp10 were replaced by Arg, Lys and Arg, possessed the highest activity among the TNF mutants, and its activity was 120-fold that of native TNF. The various biological activities of TNF were signaled through 2 distinct receptors, p55 and p75. Although cytotoxicity was reported to involve mainly p55, this differentiation-inducing activity was not well understood. The fact that the affinity of TNF 471 was higher to p55 and lower to p75 than that of native TNF by a binding competition assay suggested that the differentiation-inducing activity was also signaled through p55. To verify this hypothesis, the human myelogenous leukemic cell line, KG-1, which scarcely expresses either receptor and does not differentiate with TNF, was transduced with the p55 or p75 gene. Subsequently p55 transfectants manifested a greater ability to differentiate; however, p75 transfectants did not differ from parental cells or from mock-transfectants. Further, the differentiation of p55 transfectants induced by TNF was reduced by the inhibitor of protein-kinase-C (PKC), staurosporine. These results indicate that the differentiation-inducing activity was signaled through the TNF receptor, p55, via PKC and that the excellent ability of TNF 471 to induce differentiation was related to its high affinity for p55.

Antigens, CD↗