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Biomedical subjects

Y Iwakura

Publications and source records attributed to Y Iwakura.

At least 91 records · Page 5Linked to original sources
PubMed1997

Suppression of concanavalin A-induced hepatitis in IFN-gamma(-/-) mice, but not in TNF-alpha(-/-) mice: role for IFN-gamma in activating apoptosis of hepatocytes.

Con A-induced hepatitis (Con A-hepatitis) is a hepatitis model in which hepatic injury is supposed to be caused by cytokines from activated T cells. To elucidate the pathogenesis of this disease, we analyzed the roles of IFN-gamma and TNF-alpha using deficient mice of these cytokines. Development of hepatitis was reduced significantly in IFN-gamma(-/-) mice, while susceptibility of TNF-alpha(-/-) mice was not changed. Interestingly, apoptotic cell death was observed in the affected livers of control or TNF-alpha(-/-) mice, but not in those of IFN-gamma(-/-) mice. Fas mRNA expression was increased in the livers of hepatitis mice, but less abundantly in those of IFN-gamma(-/-) mice. Since apoptosis of liver cells was rarely observed in Con A-treated lpr/lpr mice, involvement of the Fas-Fas ligand system in this apoptotic process was suggested. These observations suggest that IFN-gamma plays a central role in Con A-hepatitis by activating Fas-induced apoptosis of liver cells.

Animals↗
PubMed1997

Resistance to fas-mediated apoptosis of peripheral T cells in human T lymphocyte virus type I (HTLV-I) transgenic mice with autoimmune arthropathy.

Transgenic mice carrying the env-pX region of human T lymphocyte virus type I (HTLV-I) develop autoimmune arthropathy in high incidence. Adopting the approach that Fas-mediated apoptosis has a critical function in the elimination of self-reactive T cells, we examined the involvement of this apoptosis in the induction of autoimmunity in HTLV-I transgenic mice. Splenic T cells derived from the transgenic mice were more resistant to apoptosis induced by anti-Fas mAb than those of the nontransgenic mice, whereas no appreciable difference in apoptosis was detected for thymocytes from either mouse's type. The resistance of transgenic T cells may be due to Tax coded in the pX region, since Tax mediates the inhibition of anti-Fas- induced apoptosis in mature T cell line, Jurkat. Among the transgenic mice, the extent of the resistance to Fas-mediated apoptosis was further enhanced in transgenic T cells with disease. These results suggest that the escape of self-reactive T cells from Fas-mediated apoptosis in the periphery, is critical for the development of autoimmune arthropathy in HTLV-I transgenic mice.

Animals↗
PubMed1997

Interleukin 18 together with interleukin 12 inhibits IgE production by induction of interferon-gamma production from activated B cells.

Interleukin 18 (IL-18), originally called interferon (IFN)-gamma-inducing factor, is a recently cloned cytokine of approximately 18 kDa synthesized by Kupffer cells and activated macrophages. The major activity associated with this molecule is the induction of IFN-gamma production from anti-CD3-activated T helper 1 cells in the presence of IL-12. B cells produce IgG1 and IgE when stimulated with anti-CD40 and IL-4. Here we show that a combination of IL-12 and IL-18 induces anti-CD40-activated B cells to produce IFN-gamma, which inhibits IL-4-dependent IgE and IgG1 production and enhances IgG2a production without inhibiting the B cell proliferative response. We also show that 24.3% of B cells became positive for cytoplasmic IFN-gamma after being stimulated with IL-12 and IL-18. Furthermore, we show that, like splenic T cells stimulated with anti-CD3, IL-12, and IL-18, B cells produced high level of IFN-gamma in response to anti-CD40, IL-12, and IL-18. Injection of a mixture of IL-12 and IL-18 into mice inoculated with Nippostrongylus brasiliensis or injected with anti-IgD induced IFN-gamma-producing cells that inhibit IgE production in them. Furthermore, B cells obtained from normal mice could develop into IFN-gamma-producing cells in IFN-gamma(-/-) host mice in response to in vivo treatment with IL-12 and IL-18. These results indicate that IFN-gamma from activated B cells differentially regulates IgG1/IgE and IgG2a responses in vitro and in vivo, indicating that B cells act as regulatory cells in the immune response. Present results suggested that injection of IL-12 and IL-18 could present a unique approach for the treatment of allergic disorders.

Animals↗
PubMed1997

Growth retardation and early death of beta-1,4-galactosyltransferase knockout mice with augmented proliferation and abnormal differentiation of epithelial cells.

Carbohydrate chains on a glycoprotein are important not only for protein conformation, transport and stability, but also for cell-cell and cell-matrix interactions. UDP-Gal:N-acetylglucosamine beta-1,4-galactosyltransferase (GalT) (EC 2.4.1.38) is the enzyme which transfers galactose (Gal) to the terminal N-acetylglucosamine (GlcNAc) of complex-type N-glycans in the Golgi apparatus. In addition, it has also been suggested that this enzyme is involved directly in cell-cell interactions during fertilization and early embryogenesis through a subpopulation of this enzyme distributed on the cell surface. In this study, GalT-deficient mice were produced by gene targeting in order to examine the pathological effects of the deficiency. GalT-deficient mice were born normally and were fertile, but they exhibited growth retardation and semi-lethality. Epithelial cell proliferation of the skin and small intestine was enhanced, and cell differentiation in intestinal villi was abnormal. These observations suggest that GalT plays critical roles in the regulation of proliferation and differentiation of epithelial cells after birth, although this enzyme is dispensable during embryonic development.

Animals↗
PubMed1996

Therapeutic effect of the anti-Fas antibody on arthritis in HTLV-1 tax transgenic mice.

We have recently demonstrated Fas-mediated apoptosis in the synovium, of patients with rheumatoid arthritis (RA) and suggested that it may be one factor responsible for the regression of RA. To examine whether the induction of apoptosis caused by anti-Fas mAb may play a potential role as a new therapeutic strategy for RA, we investigated the effect of anti-Fas mAb (RK-8) on synovitis in an animal model of RA, the human T cell leukemia virus type I (HTLV-1) tax transgenic mice. We report here that administration of anti-Fas mAb into mice intra-articularly improved the paw swelling and arthritis within 48 h. Immunohistochemical study and in vitro culture studies showed that 35% of synovial fibroblasts, 75% of mononuclear cells, and some of polymorphonuclear leukocytes infiltrating in synovium underwent apoptosis by anti-Fas mAb. In situ nick end labeling analysis and electron microscope analysis clearly showed that many cells in synovium were induced apoptosis by anti-Fas mAb administration. However, local administration of anti-Fas mAb did not produce systemic side effects. Results demonstrated that administration of anti-Fas mAb in arthritic joints of the HTLV-1 tax transgenic mice produced improvement of arthritis. These findings suggest that local administration of anti-Fas mAb may represent a useful therapeutic strategy for proliferative synovitis such as RA.

Alanine Transaminase↗
PubMed1996

Molecular characterization of extrachromosomal circular DNAs from differentiating embryonic stem cells.

Embryonic E14 stem cells were differentiated to parietal yolksac-like flat cells in vitro in the absence of added feeders and LIF (Leukemia Inhibitory Factor). We cloned circular DNAs from the differentiating E14 cells. Out of 9 DNA inserts with the unique sequence, one clone showed a chromosomal rearrangement which could have occurred between a pair of short inverted repeats. Recombination mechanism is discussed in view of two other circularization events of the flanking sequences between short inverted repeats shown in differentiated P19 embryonal carcinoma cells.

Base Sequence↗
PubMed1995

Autoimmunity induction by human T cell leukemia virus type 1 in transgenic mice that develop chronic inflammatory arthropathy resembling rheumatoid arthritis in humans.

We recently reported on an inflammatory arthropathy resembling rheumatoid arthritis that develops in high incidence among transgenic mice that carry the env-pX region of the human T cell leukemia virus type 1 genome. In an effort to elucidate the pathogenesis of this disease, we found that genes for inflammatory cytokines, including IL-1 alpha, IL-1 beta, IL-6, TNF-alpha, transforming growth factor-beta 1, IFN-gamma, and IL-2, as well as MHC genes were activated in transgenic joints. Serum levels of IL-1 beta and IL-6 were also elevated. Interestingly, these mice produced Ab against IgG, type II collagen (IIC), and heat shock proteins accompanied by IgG hypergammaglobulinemia. The cellular immune response to IIC as well as that to heat shock proteins were activated. Moreover, these mice became immunologically responsive to exogenously administered IIC and developed arthritis, in contrast to their nontransgenic littermates, which showed little response to IIC. Taken together, the results suggest that human T cell leukemia virus type 1 can cause immune system hyperreactivity and induce autoimmunity. The possibility that elevated cytokine and/or MHC gene expression are involved in the development of autoimmunity and arthropathy are discussed.

Animals↗
PubMed1995

Augmentation of c-fos and c-jun expression in transgenic mice carrying the human T-cell leukemia virus type-I tax gene.

To analyze the effect of human T-cell leukemia virus type I (HTLV-I) on cellular gene expression and its relation to tumorigenesis, two lines of transgenic mice carrying the long terminal repeat (LTR)-env-pX-LTR regions of the HTLV-I genome were produced. The transgene was expressed in many organs, including the brain, salivary gland, spleen, thymus, skin, muscle, and mammary gland. We found that the expression of the c-fos and c-jun genes, but not of the lyn and c-myc genes, was augmented 2- to 20-fold in histologically normal skin and muscle of these mice. The augmentation was tissue specific, suggesting the involvement of a cellular factor in the transgene action. In these mice, a three to seven times higher incidence of tumors was seen as compared with the control mice. These tumors included mesenchymal tumors, such as fibrosarcoma, neurofibroma, and lipoma, and adenocarcinomas of the mammary gland, salivary gland, and lung. The c-fos and c-jun genes were also activated in these tumors. The possible roles of elevated c-fos and c-jun gene expression in tumorigensis are discussed.

Animals↗
PubMed1995

A human GM-CSF receptor expressed in transgenic mice stimulates proliferation and differentiation of hemopoietic progenitors to all lineages in response to human GM-CSF.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) mainly stimulates proliferation and maturation of myeloid progenitor cells. Although the signal transduction pathways triggered by GM-CSF receptor (GMR) have been extensively characterized, the roles of GMR signals in differentiation have remained to be elucidated. To examine the relationship between receptor expression and differentiation of hemopoietic cells, we used transgenic mice (Tg-mice) that constitutively express human (h) GMR at almost all stages of hemopoietic cell development. Proliferation and differentiation of hemopoietic progenitors in bone marrow cells from these Tg-mice were analyzed by methylcellulose colony formation assay. High affinity GMR interacts with GM-CSF in a species-specific manner, therefore one can analyze the effects of hGMR signals on differentiation of mouse hemopoietic progenitors using hGM-CSF. Although mouse (m) GM-CSF yielded only GM colonies, hGM-CSF supported various types of colonies including GM, eosinophil, mast cell, erythrocyte, megakaryocyte, blast cell, and mixed hemopoietic colonies. Thus, the effects of hGM-CSF on colony formation more closely resembled mIL-3 than those of mGM-CSF. In addition, hGM-CSF generated a much larger number of blast cell colonies and mixed cell colonies than did mIL-3. hGM-CSF also generated erythrocyte colonies in the absence of erythropoietin. Therefore, GM-CSF apparently has the capacity to promote growth of cells of almost all hemopoietic cell lineages, if functional hGMR is present.

Animals↗
PubMed1993

Structural changes in the N-linked sugar chains of serum immunoglobulin G of HTLV-I transgenic mice.

IgGs were purified from the sera of HTLV-I transgenic and nontransgenic mice. Comparative studies of the N-linked sugar chains released by hydrazinolysis revealed that their structures of transgenic IgG are quite different from those of nontransgenic IgG. Although both IgGs contained biantennary complex-type oligosaccharides, transgenic IgG had more agalactosylated forms (45%) than those from nontransgenic IgG (28%), just as was found in patients with rheumatoid arthritis (RA). Since these transgenic mice express arthritis similar to RA, it will be a useful model to investigate the relationship between the galactosylation of IgG and the development of RA.

Animals↗
PubMed1993

Inflammatory polyarthritis in mice transgenic for human T cell leukemia virus type I.

OBJECTIVE: We have recently reported that arthropathy develops in high incidence among transgenic mice carrying the pX region of human T cell leukemia virus type I (HTLV-I). In the present study, the histopathologic features of the joints in these mice were examined in order to compare the animal disease with rheumatoid arthritis (RA) in humans. METHODS: Paraffin sections of limbs (right and left fingers, wrists, elbows, shoulders, toes, knees, and ankles) were stained with hematoxylin and eosin, periodic acid-Schiff, azan-Mallory, or phosphotungstic acid hematoxylin, and examined by light microscopy. RESULTS: Abnormalities of the limbs began to occur as early as 3 weeks of age, and the incidence gradually increased until the mice were 12 months old. The incidence of arthropathy was 22% (48 of 217) at 3 months of age and 28% (18 of 64) at 6 months. The severity of the histopathologic changes in the joints of the transgenic mice ranged from grade I to grade IV. CONCLUSION: The major histopathologic features in the joints of HTLV-I transgenic mice are similar to those in humans with RA. Thus, these mice may represent a useful model for the study of the disease in humans.

Animals↗
PubMed1993

Aberrant tissue specific expression of the transgene in transgenic mice that carry the hepatitis B virus genome defective in the X gene.

The control mechanisms for the transgene expression in mice that carry the hepatitis B virus genome defective in the polymerase and X genes were analyzed. Ten lines of transgenic mouse were established, and in seven lines the surface and e antigens were detected in the serum. In transgenic mice from five lines examined, the transgene was markedly expressed in a broad spectrum of tissues including the kidney, heart, brain, muscle and intestine, but only poorly in the liver. In the kidney and heart the 3.5 kb and 2.1 kb mRNAs were expressed, whereas only the 0.8 kb and 4.0 kb mRNAs were detected in the testis and brain, respectively, suggesting that each of the mRNAs was transcribed through a different control mechanism. The surface, e and core antigens accumulated in the kidney and heart. DNA was hypomethylated at a region closely downstream of the enhancer in the liver, kidney and heart, and a DNase I hypersensitive site was detected upstream of the enhancer in these tissues. In the testis, however, the whole transgene was hypomethylated and the DNase I hypersensitive site was closer to the enhancer. These differences may be relevant to the preferential expression of the 0.8 kb mRNA in the testis, but cannot explain the inefficiency of transgene expression in the liver. Our observations suggest that the X protein is required for efficient expression of the viral gene in the liver but not in other tissues.

Animals↗
PubMed1992

RNA packaging signal of human immunodeficiency virus type 1.

Cells infected with a recombinant vaccinia virus carrying the gag and pol regions of the human immunodeficiency virus type 1 genome (Vac-gag/pol) released human immunodeficiency virus (HIV)-like particles containing HIV-specific RNA. However, cells infected with another recombinant vaccinia, Vac-gag/pol-dP, derived through the deletion of an 85-base region (nucleotide positions 679-763) of the HIV genome between the primer binding site and the gag initiation codon of Vac-gag/pol, produced HIV-like particles devoid of the HIV-specific RNA. This 85-base deletion was suggested to cause the collapse of a stable stem-loop structure of 46 bases (751-796) around the gag initiation codon. To examine the role of the stem-loop structure in the packaging of RNAs, we constructed a vaccinia vector plasmid that carried this 46-base sequence followed by the Sendai virus nucleocapsid (NP) gene. When both Vac-gag/pol-dP and this plasmid were introduced into cells, HIV-like particles released from the cells contained the NP gene RNA. However, another vaccinia vector plasmid, which carried the 46-base sequence in the midst of the NP gene, could not supply RNA for incorporation into HIV-like particles. Computer analysis of this plasmid sequence suggested that the 46-base sequence cannot form the stem-loop structure. These findings suggest that the stem-loop structure formed by the 46-base sequence is crucial as a packaging signal.

Base Sequence↗
PubMed1992

The induction of cataracts by HIV-1 in transgenic mice.

OBJECTIVE: To elucidate the tissue specificity of the expression of HIV-1 genes in an animal and its pathological effects on these tissues. DESIGN AND METHODS: Transgenic mice carrying a defective HIV-1 genome were bred in order to overcome the host-range barrier of this virus. RESULTS: mRNA specific to the transgene was detected in the eyes and the spleen, and, in smaller quantities, in the thymus and the brain. Interestingly, many of the transgenic mice developed cataracts at 3-6 months of age. Swelling and vacuolation of the lens fiber cells were marked, but the epithelial cells of the lens were less affected. HIV antigens were detected in the lens fiber cells and the retina by immunological staining. Accumulation of large amounts of p24 Gag antigen was demonstrated in the affected lens by immunoblot analysis, while negligible Env or other viral proteins was detected. Although accumulation of the Gag protein was also detected in the skin and the brain, no apparent abnormality was observed in these tissues. CONCLUSIONS: Preferential expression of the HIV genes in the eyes, skin, brain and lymphoid tissues was demonstrated. The accumulation of the Gag protein is suggested to have detrimental effects on lens fiber cells, causing cataracts.

Acquired Immunodeficiency Syndrome↗