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Biomedical subjects

I Miyajima

Publications and source records attributed to I Miyajima.

At least 19 recordsLinked to original sources
PubMed1997

IgE regulates mouse basophil Fc epsilon RI expression in vivo.

The binding of IgE to high-affinity IgE receptors (Fc epsilon RI) on the surface of mast cells and basophils primes these cells to secrete a panel of proinflammatory mediators upon subsequent exposure to specific Ag. We now find that the level of Fc epsilon RI expression on bone marrow basophils in mice infected with the nematode Strongyloides venezuelensis exhibits a strong positive correlation with the serum concentration of IgE, as was previously reported for human blood basophils. Moreover, the administration of IgE in vivo can significantly upregulate Fc epsilon RI expression on mouse basophils, and genetically IgE-deficient (IgE -/-) mice exhibit a dramatic (approximately 81%) reduction of basophil Fc epsilon RI expression compared with the corresponding normal (IgE +/+) mice. The finding that IgE can be a major regulator of mouse basophil Fc epsilon RI expression in vivo identifies a potentially important mechanism for enhancing the expression of effector cell function in IgE-dependent allergic reactions or immunologic responses to parasites.

Animals↗
PubMed1997

Systemic anaphylaxis in the mouse can be mediated largely through IgG1 and Fc gammaRIII. Assessment of the cardiopulmonary changes, mast cell degranulation, and death associated with active or IgE- or IgG1-dependent passive anaphylaxis.

We attempted to elicit active anaphylaxis to ovalbumin, or passive IgE- or IgG1-dependent anaphylaxis, in mice lacking either the Fc epsilonRI alpha chain or the FcR gamma chain common to Fc epsilonRI and Fc gammaRI/III, or in mice lacking mast cells (KitW/ KitW-v mice), and compared the responses to those in the corresponding wild-type mice. We found that the FcR gamma chain is required for the death, as well as for most of the pathophysiological changes, associated with active anaphylaxis or IgE- or IgG1-dependent passive anaphylaxis. Moreover, some of the physiological changes associated with either active, or IgG1-dependent passive, anaphylactic responses were significantly greater in Fc epsilonRI alpha chain -/- mice than in the corresponding normal mice. Finally, while both KitW/KitW-v and congenic +/+ mice exhibited fatal active anaphylaxis, mast cell-deficient mice exhibited weaker physiological responses than the corresponding wild-type mice in both active and IgG1-dependent passive systemic anaphylaxis. Our findings strongly suggest that while IgE antibodies and Fc epsilonRI may influence the intensity and/or kinetics of some of the pathophysiological changes associated with active anaphylaxis in the mouse, the mortality associated with this response can be mediated largely by IgG1 antibodies and Fc gammaRIII.

Anaphylaxis↗
PubMed1997

Absence of Fc epsilonRI alpha chain results in upregulation of Fc gammaRIII-dependent mast cell degranulation and anaphylaxis. Evidence of competition between Fc epsilonRI and Fc gammaRIII for limiting amounts of FcR beta and gamma chains.

In mouse mast cells, both Fc epsilonRI and Fc gammaRIII are alpha beta gamma2 tetrameric complexes in which different alpha chains confer IgE or IgG ligand recognition while the signaling FcR beta and gamma chains are identical. We used primarily noninvasive techniques (changes in body temperature, dye extravasation) to assess systemic anaphylactic responses in nonanesthetized wild-type, Fc epsilonRI alpha chain -/- and FcR gamma chain -/- mice. We confirm that systemic anaphylaxis in mice can be mediated largely through IgG1 and Fc gammaRIII and we provide direct evidence that these responses reflect activation of Fc gammaRIII rather than Fc gammaRI. Furthermore, we show that Fc gammaRIII-dependent responses are more intense in normal than in congenic mast cell-deficient KitW/KitW-v mice, indicating that Fc gammaRIII responses have mast cell-dependent and -independent components. Finally, we demonstrate that the upregulation of cell surface expression of Fc gammaRIII seen in Fc epsilonRI alpha chain -/- mice corresponds to an increased association of Fc gammaRIII alpha chains with FcR beta and gamma chains and is associated with enhanced Fc gammaRIII-dependent mast cell degranulation and systemic anaphylactic responses. Therefore, the phenotype of the Fc epsilonRI alpha chain -/- mice suggests that expression of Fc epsilonRI and Fc gammaRIII is limited by availability of the FcR beta and gamma chains and that, in normal mice, changes in the expression of one receptor (Fc epsilonRI) may influence the expression of functional responses dependent on the other (Fc gammaRIII).

Anaphylaxis↗
PubMed1997

IgE enhances mouse mast cell Fc(epsilon)RI expression in vitro and in vivo: evidence for a novel amplification mechanism in IgE-dependent reactions.

The binding of immunoglobulin E (IgE) to high affinity IgE receptors (Fc(epsilon)RI) expressed on the surface of mast cells primes these cells to secrete, upon subsequent exposure to specific antigen, a panel of proinflammatory mediators, which includes cytokines that can also have immunoregulatory activities. This IgE- and antigen-specific mast cell activation and mediator production is thought to be critical to the pathogenesis of allergic disorders, such as anaphylaxis and asthma, and also contributes to host defense against parasites. We now report that exposure to IgE results in a striking (up to 32-fold) upregulation of surface expression of Fc(epsilon)RI on mouse mast cells in vitro or in vivo. Moreover, baseline levels of Fc(epsilon)RI expression on peritoneal mast cells from genetically IgE-deficient (IgE -/-) mice are dramatically reduced (by approximately 83%) compared with those on cells from the corresponding normal mice. In vitro studies indicate that the IgE-dependent upregulation of mouse mast cell Fc(epsilon)RI expression has two components: an early cycloheximide-insensitive phase, followed by a later and more sustained component that is highly sensitive to inhibition by cycloheximide. In turn, IgE-dependent upregulation of Fc(epsilon)RI expression significantly enhances the ability of mouse mast cells to release serotonin, interleukin-6 (IL-6), and IL-4 in response to challenge with IgE and specific antigen. The demonstration that IgE-dependent enhancement of mast cell Fc(epsilon)RI expression permits mast cells to respond to antigen challenge with increased production of proinflammatory and immunoregulatory mediators provides new insights into both the pathogenesis of allergic diseases and the regulation of protective host responses to parasites.

Animals↗
PubMed1997

Prevalence of hepatitis C antibodies in health care personnel.

To determine the prevalence of hepatitis C virus (HCV) infection in health care personnel in an HCV endemic area, we conducted a seroprevalence study of 1638 Kurume University Hospital physicians, nurses, laboratory staff, and clerical staff (560 men, 1078 women). Antibody to HCV (anti-HCV) was found in 2.8% (46) of subjects and hepatitis B surface antigen was found in 1.1% (18). The anti-HCV positive rate in health care personnel was no higher than reported in the general population of Fukuoka prefecture in Kyushu, Japan. There were no significant differences in anti-HCV positive rate by occupation. However, the prevalence of anti-HCV positive individuals increased significantly as age and length of time in an occupation increased. Anti-HCV positive rate in health care personnel was probably not related to length of time in an occupation. The data suggest that HCV infection is not easily transmitted to health care personnel in an HCV endemic area.

Adult↗
PubMed1996

Interferon accumulation in cirrhotic rat liver.

In patients with chronic hepatitis C, the therapeutic effect of interferon (IFN) is influenced by the progression of liver disease. In a previous study, we showed that 2',5'-oligoadenylate synthetase activity in the liver homogenate was significantly lower in cirrhotic rats than in controls after injection of murine IFN. To determine the reason for this decrease, we injected IFN into rats with thioacetamide-induced cirrhosis and used microautoradiography with human lymphoblastoid interferon ([125I]LyIFN). Accumulation of [125I]LyIFN in cirrhotic rat livers was approximately half of that in control rats (2880 +/- 900 vs 5770 +/- 600 mm2, P < 0.01). In the cirrhotic rat livers there were few grains on the hepatocytes, but many on collagen fibres. These results suggest that binding of IFN to its hepatocyte receptors is hindered in the presence of cirrhosis. The decreased amount of IFN reaching hepatocytes may contribute to the poor responses to IFN seen in patients with cirrhosis.

Animals↗
PubMed1996

Evaluation of interferon treatment in cirrhotic patients with hepatitis C.

The aim of this study was to examine the effects of interferon on cirrhotic patients with hepatitis C and the incidence of adverse reactions. The subjects were 35 cirrhotic patients, and 29 chronic active hepatitis patients without cirrhosis (CAH) served as controls. The cirrhotic patients received 3 or 6 million units of human lymphoblastoid interferon daily for one or two weeks and then three times a week for 22 or 23 weeks, while the CAH patients received 6 million units daily for 2 weeks and then three times a week for 14 or 16 weeks. Discontinuation of interferon treatment or dose reduction was required in the 7 cirrhotic patients. The most frequent reason was thrombocytopenia. Dose reduction alone was necessary in two CAH patients. Five cirrhotic patients (14.3%) and nine CAH patients (31.0%) were classified as complete responders to interferon treatment. In all five complete responders with cirrhosis, the hepatitis C virus RNA level before treatment was less than 5 log copies/50 microliters. The results of this study confirm the beneficial effect of interferon in selected patients with cirrhosis on basis of pre-treatment virus levels and platelet count.

Base Sequence↗
PubMed1996

Sequential interferon-alpha and beta treatment in patients with chronic hepatitis C.

To assess the effectiveness and side effects of sequential interferon (IFN)-alpha and beta treatment for patients with chronic hepatitis C, 25 patients were enrolled in a trial of this regimen. The patients were given 6 million units (MU) of natural human INF-beta daily for 2 weeks followed by 6 MU of natural human IFN-alpha three times a week for 10 to 22 weeks. Serum alanine aminotransferase (ALT) levels normalized for at least 24 weeks in 10 patients (40%), of whom 4 (40%) had no detectable serum hepatitis C virus (HCV) RNA. Three variables were significant in predicting a sustained response: a low serum HCV RNA level, a low Knodell's fibrosis score, and a low indocyanine green retention rate at 15 minutes. Elevated serum ALT and proteinurea were observed with IFN-beta treatment but these side effects were mild and disappeared when INF-beta treatment ended. While all patients completed the entire regimen, we concluded that sequential IFN-alpha and beta treatment provides no additional antiviral effects in chronic hepatitis C.

Alanine Transaminase↗
PubMed1995

The murine interleukin-3 receptor alpha subunit gene: chromosomal localization, genomic structure, and promoter function.

The interleukin-3 receptor (IL-3R) is composed of alpha and beta subunits, members of the class I cytokine receptor family. Here we describe isolation and characterization of the chromosomal gene for the mouse IL-3R alpha subunit (mIL-3R alpha). Whereas the human IL-3R alpha gene is tightly linked with the granulocyte-macrophage colony-stimulating factor receptor alpha subunit (GM-CSFR alpha) gene in the pseudoautosomal region of the X and Y chromosomes, the mIL-3R alpha gene (II3ra) is located in the proximal region of mouse chromosome 14, separated from the mouse GM-CSFR alpha gene, which is on chromosome 19. The mIL-3R alpha gene spans about 10 kb and is divided into 12 exons. All the exon-intron boundaries possess the splicing junction consensus sequences (5'GT-AG3'), and the whole genomic structure is similar to those of the previously reported class I cytokine receptor genes. There are two major transcription initiation sites that are located at 215 and 188 nucleotides upstream of the initiator codon. The promoter region is GC-rich and contains potential binding sites for GATA, Ets, c-myb,, Sp1, Ap-2, and G-C boxes, but not a typical TATA or CAAT sequence. A fusion gene containing 0.8 kb of the 5' noncoding sequence linked to the firefly luciferase gene directed the transcription in mouse mast cells but not in fibroblasts or T cells, suggesting that this promoter functions in a cell type-specific manner. Further sequential deletion of the 5' region suggests two potential regulatory regions for transcription of the mIL-3R alpha gene.

3T3 Cells↗
PubMed1995

Decrease of interferon-induced 2',5'-oligoadenylate synthetase activity in cirrhotic rat liver.

We evaluated the effect of hepatic fibrosis on the induction of hepatic 2',5'-oligoadenylate synthetase (2-5AS) by interferon (IFN) in a rat model of liver cirrhosis, induced with thioacetamide. Although there was no difference in serum 2-5AS activity between the control and cirrhotic rats given murine IFN, 2-5AS activity in the liver homogenates of cirrhotic rats was significantly lower than in the controls (105 +/- 18.5 vs. 171 +/- 10.2 pmol/micrograms, p < 0.01). These results suggested that hepatic fibrosis attenuated the effect of IFN and one of the reasons for this may be the decreased induction of hepatic 2-5AS activity after IFN administration in the presence of a cirrhotic liver.

2',5'-Oligoadenylate Synthetase↗
PubMed1993

Ligand-dependent activation of chimeric receptors with the cytoplasmic domain of the interleukin-3 receptor beta subunit (beta IL3).

beta IL3 (formerly known as AIC2A), a beta subunit of the murine interleukin-3 receptor (IL-3R), is not only required for formation of the high affinity receptor but is also important for signal transduction. To examine the function of beta IL3 in signal transduction, we constructed several chimeric receptors consisting of the intracellular portion of beta IL3 and the extracellular portion of other members of the cytokine receptor superfamily, i.e. the human interleukin-2 receptor beta chain (hIL-2R beta), the human interleukin-4 receptor (hIL-4R), and the murine erythropoietin receptor (mEpoR). These chimeric receptors and normal cytokine receptors were expressed in an IL-3-dependent murine pro-B cell line, Ba/F3, and an IL-2-dependent murine T cell line, CTLL2. Regardless of the origin of the extracellular domain, these chimeric receptors were functional in Ba/F3 cells; they stimulated proliferation and induced tyrosine phosphorylation in response to the cytokine corresponding to the extracellular domain. However, the response of transfectants expressing chimeric receptors was similar to, but not identical with, the response of Ba/F3 cells to mIL-3. We present evidence that the IL-4R and EpoR probably have an additional component which is involved in signal transduction.

Animals↗
PubMed1992

Critical cytoplasmic domains of the common beta subunit of the human GM-CSF, IL-3 and IL-5 receptors for growth signal transduction and tyrosine phosphorylation.

The high-affinity receptors for human granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 3 (IL-3) and interleukin 5 (IL-5) are composed of two distinct subunits, alpha and beta c. The alpha subunits are specific for each cytokine, whereas the beta subunit (beta c) is shared by the three receptors and is an essential component of signal transduction. We have made a series of mutant beta c cDNAs that delete various regions of the cytoplasmic domain and examined the function of these mutants by coexpressing them with the alpha subunit of the human GM-CSF receptor (hGMR) in an IL-3-dependent mouse pro-B cell line BaF3. Two domains in the membrane-proximal portion of beta c were found to be important for transducing the hGM-CSF-mediated growth signals: one domain between Arg456 and Phe487 appears to be essential for proliferation, and the second domain between Val518 and Asp544 enhances the response to GM-CSF, but is not absolutely required for proliferation. The region between Val518 and Leu626 was responsible for major tyrosine phosphorylation of 95 and 60 kDa proteins. Thus, beta c-mediated major tyrosine phosphorylation of these proteins was apparently separated from proliferation. However, the beta 517 mutant lacking residues downstream of Val518 transmitted a herbimycin-sensitive proliferation signal, suggesting that beta 517 still activates a tyrosine kinase(s). We also evaluated the role of the cytoplasmic domain of the GMR alpha subunit and the results suggest that it is involved in the hGM-CSF-mediated signal transduction, but is not essential.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1991

SGV1 encodes a CDC28/cdc2-related kinase required for a G alpha subunit-mediated adaptive response to pheromone in S. cerevisiae.

The GPA1 gene of S. cerevisiae encodes a G alpha subunit that plays a positive role in the transduction of signals stimulating recovery from pheromone-induced cell cycle arrest. The GPA1Val50 mutation, in which Gly-50 is replaced by valine, causes hyperadaptation to pheromone. However, GPA1Val50 cells do not recover from division arrest in the absence of both CLN1 and CLN3, which encode G1 cyclins, indicating that the recovery-promoting activity of GPA1Val50 requires the function of G1 cyclins. An sgv1 mutation suppresses the hyperadaptive response caused by GPA1Val50 and also confers cold- and temperature-sensitive growth. The SGV1 gene encodes an apparent protein kinase homologous to CDC28/cdc2 kinase: SGV1 is 42% identical to CDC28. The activated mutation, CLN3-2, partially suppresses the growth defect of sgv1, suggesting that the SGV1 and CLN3 proteins may act in the same growth control pathway.

Amino Acid Sequence↗
PubMed1989

GPA1Val-50 mutation in the mating-factor signaling pathway in Saccharomyces cerevisiae.

The GPA1 gene of Saccharomyces cerevisiae encodes a protein that is highly homologous to the alpha subunit of mammalian hetrotrimeric G proteins and is essential for haploid cell growth. A mutation of the GPA1 protein, GPA1Val-50, in which Gly-50 was replaced by valine, could complement the growth defect of a GPA1 disruption, gpal::HIS3. However, cells with gpa1::HIS3 expressing the GPA1Val-50 protein were supersensitive to alpha-factor in a short-term incubation but resumed growth after long-term incubation even after exposure to high concentrations of alpha-factor. The former phenotype associated with GPA1Val-50 is recessive, and the latter phenotype is dominant to GPA1+. The supersensitivity of GPA1Val-50 to alpha-factor was dependent on STE2 and STE4, which demonstrates that this GPA1Val-50-produced phenotype requires the mating-factor receptor and the beta subunit of the G protein. The double mutant of sst2-1 GPA1Val-50 recovered from division arrest, which suggested that SST2 is not required for recovery of the GPA1Val-50 mutant.

Amino Acid Sequence↗
PubMed1988

Isolation of a second yeast Saccharomyces cerevisiae gene (GPA2) coding for guanine nucleotide-binding regulatory protein: studies on its structure and possible functions.

In a previous paper, we demonstrated that a gene coding for a protein homologous to the alpha subunit of mammalian guanine nucleotide-binding regulatory (G) proteins occurs in Saccharomyces cerevisiae. The gene, designated GPA1, encodes a protein (GP1 alpha) of 472 amino acids with a calculated Mr of 54,075. Here we report the isolation of another G-protein-homologous gene, GPA2, which encodes an amino acid sequence of 449 amino acid residues with a Mr of 50,516. The predicted primary structure of the GPA2-encoded protein (GP2 alpha) is homologous to mammalian G proteins [inhibitory and stimulatory G proteins (Gi and Gs, respectively), a G protein of unknown function (Go), and transducins (Gt)] as well as yeast GP1 alpha. When aligned with the alpha subunit of Gi (Gi alpha) to obtain maximal homology, GP2 alpha was found to contain a stretch of 83 additional amino acid residues near the NH2 terminus. The gene was mapped in chromosome V, close to the centromere. Haploid cells carrying a disrupted GPA2 gene are viable. Cells carrying a high copy number of plasmid GPA2 (YEpGPA2) had markedly elevated levels of cAMP and could suppress a temperature-sensitive mutation of RAS2. These results suggest that GPA2 may be involved in the regulation of cAMP levels in S. cerevisiae.

Amino Acid Sequence↗
PubMed1988

Suppressors of a gpa1 mutation cause sterility in Saccharomyces cerevisiae.

The Saccharomyces cerevisiae GPA1 gene encodes a protein highly homologous to the alpha subunit of mammalian G proteins and is essential for haploid cell growth. We have selected 77 mutants able to suppress the lethality resulting from disruption of GPA1 (gpa1::HIS3). Two strains bearing either of two recessive mutations, sgp1 and sgp2, in combination with the disruption mutation, showed a cell type nonspecific sterile phenotype, yet expressed the major alpha-factor gene (MF alpha 1) as judged by the ability to express a MF alpha 1-lacZ fusion gene. The sgp1 mutation was closely linked to gpa1::HIS3 and probably occurred at the GPA1 locus. The sgp2 mutation was not linked to GPA1 and was different from the previously identified cell type nonspecific sterile mutations (ste4, ste5, ste7, ste11 and ste12). sgp2 GPA1 cells showed a fertile phenotype, indicating that the mating defect caused by sgp2 is associated with the loss of GPA1 function. While expression of a FUS1-lacZ fusion gene was induced in wild-type cells by the addition of alpha-factor, mutants bearing sgp1 or sgp2 as well as gpa1::HIS3 constitutively expressed FUS1-lacZ. These observations suggest that GPA1 (SGP1) and SGP2 are involved in mating factor-mediated signal transduction, which causes both cell cycle arrest in the late G1 phase and induction of genes necessary for mating such as FUS1.

Cell Cycle↗
PubMed1987

GPA1, a haploid-specific essential gene, encodes a yeast homolog of mammalian G protein which may be involved in mating factor signal transduction.

GPA1 protein of Saccharomyces cerevisiae is homologous to the alpha subunit of mammalian G protein. GPA1 transcript was found in haploid cells but was not detected in diploid cells. Disruption of GPA1 resulted in a haploid-specific lethal phenotype, indicating that GPA1 is a haploid-specific essential gene for cell growth. Upon regulation of expression of GPA1 by the galactose-inducible GAL1 promoter, the loss of GPA1 function was found to lead to cell-cycle arrest at the late G1 phase. Mutants that suppress the lethality of the gpa1::HIS3 mutation showed a sterile phenotype that was not cell-type-specific. These results suggest that GPA1 protein may control the signal for mating-factor-mediated cell-cycle arrest.

Cell Cycle↗