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T Taga

Publications and source records attributed to T Taga.

At least 91 records · Page 5Linked to original sources
PubMed1996

Accelerated Nerve Regeneration in Mice by upregulated expression of interleukin (IL) 6 and IL-6 receptor after trauma.

In this study we aimed to examine a role for interleukin 6 (IL-6) and its receptor (IL-6R) in peripheral nerve regeneration in vivo. We first observed that cultured mouse embryonic dorsal root ganglia exhibited dramatic neurite extension by simultaneous addition of IL-6 and soluble IL-6R (sIL-6R), a complex that is known to interact with and activate a signal transducing receptor component, gp130. After injury in the hypoglossal nerve in adult mice by ligation, immunoreactivity to IL-6 was upregulated in Schwann cells at the lesional site as well as in the cell bodies of hypoglossal neurons in the brain stem. In the latter, upregulation of the immunoreactivity to IL-6R was also observed. Regeneration of axotomized hypoglossal nerve in vivo was significantly retarded by the administration of anti-IL-6R antibody. Surprisingly, accelerated regeneration of the axotomized nerve was achieved in transgenic mice constitutively expressing both IL-6 and IL-6R, as compared with nontransgenic controls. These results suggest that the IL-6 signal may play an important role in nerve regeneration after trauma in vivo.

Animals↗
PubMed1996

Cardiotrophin-1 activates a distinct form of cardiac muscle cell hypertrophy. Assembly of sarcomeric units in series VIA gp130/leukemia inhibitory factor receptor-dependent pathways.

Cardiotrophin-1 (CT-1) was recently isolated by expression cloning based on its ability to induce an increase in cell size in neonatal rat ventricular cardiomyocytes. Sequence similarity data suggested that CT-1 is a novel member of a family of structurally related cytokines sharing the receptor component gp130. The present study documents that gp130 is required for CT-1 signaling in cardiomyocytes, by demonstrating that a monoclonal anti-gp130 antibody completely inhibits c-fos induction by CT-1. Similarly, a leukemia inhibitory factor receptor subunit beta (LIFRbeta) antagonist effectively blocks the CT-1 induction of c-fos, indicating a requirement for LIFRbeta in the hypertrophic response, as well. Upon stimulation with CT-1, both gpl30 and the LIFRbeta are tyrosine-phosphorylated, providing further evidence that CT-1 signals through the gp130/LIFRbeta heterodimer in cardiomyocytes. CT-1 induces a hypertrophic response in cardiomyocytes that is distinct from the phenotype seen after alpha-adrenergic stimulation, both with regard to cell morphology and gene expression pattern. Stimulation with CT-1 results in an increase in cardiac cell size that is characterized by an increase in cell length but no significant change in cell width. Confocal laser microscopy of CT-1 stimulated cells reveals the assembly of sarcomeric units in series rather than in parallel, as seen after alpha-adrenergic stimulation. CT-1 induces a distinct pattern of immediate early genes, and up-regulates the atrial natriuretic factor (ANF) gene, but does not affect skeletal alpha-actin or myosin light chain-2v expression. As evidenced by nuclear run-on transcription assays, both CT-1 and alpha-adrenergic stimulation lead to an increase in ANF gene transcription. Transient transfection analyses document that, in contrast to alpha-adrenergic stimulation, the CT-1 responsive cis-regulatory elements are located outside of the proximal 3 kilobase pairs of the ANF 5'-flanking region. These studies indicate that CT-1 can activate a distinct form of myocardial cell hypertrophy, characterized by the promotion of sarcomere assembly in series, via gpl30/LIFRbeta-dependent signaling pathways.

Actins↗
PubMed1996

Erythropoietin-independent erythrocyte production: signals through gp130 and c-kit dramatically promote erythropoiesis from human CD34+ cells.

Erythropoietin (EPO) is the primary humoral regulator of erythropoiesis and no other factor has previously been reported to support proliferation and terminal maturation of erythroid cells from hemopoietic stem cells. Here we show that stimulation of glycoprotein (gp130) by a combination of recombinant human soluble interleukin 6 receptor (sIL-6R) and IL-6 but not sIL-6R or IL-6 alone can support proliferation, differentiation, and terminal maturation of erythroid cells in the absence of EPO from purified human CD34+ cells in suspension culture containing stem cell factor (SCF). A number of erythroid bursts and mixed erythroid colonies also developed in methylcellulose culture under the same combination. The addition of anti-gp130 monoclonal antibodies but not anti-EPO antibody to the same culture completely abrogated the generation of erythroid cells. These results clearly demonstrate that mature erythroid cells can be emerged from hemopoietic progenitors without EPO in vitro. Together with the previous reports that human sera contain detectable levels of sIL-6R, IL-6, and SCF, current data suggest that gp130 signaling in association with c-kit activation may play a role in human erythropoiesis in vivo.

Antigens, CD↗
PubMed1996

Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders.

gp130 is a ubiquitously expressed signal-transducing receptor component shared by interleukin 6, interleukin 11, leukemia inhibitory factor, oncostatin M, ciliary neurotrophic factor, and cardiotrophin 1. To investigate physiological roles of gp130 and to examine pathological consequences of a lack of gp130, mice deficient for gp130 have been prepared. Embryos homozygous for the gp130 mutation progressively die between 12.5 days postcoitum and term. On 16.5 days postcoitum and later, they show hypoplastic ventricular myocardium without septal and trabecular defect. The subcellular ultrastructures in gp130-/- cardiomyocytes appear normal. The mutant embryos have greatly reduced numbers of pluripotential and committed hematopoietic progenitors in the liver and differentiated lineages such as T cells in the thymus. Some gp130-/- embryos show anemia due to impaired development of erythroid lineage cells. These results indicate that gp130 plays a crucial role in myocardial development and hematopoiesis during embryogenesis.

Animals↗
PubMed1996

Complementary tissue-specific expression of LIF and LIF-receptor mRNAs in early mouse embryogenesis.

The maintenance of pluripotential embryonic stem (ES) cells is dependent on the cytokine LIF. This report documents the mRNA expression profiles of LIF and the two components of the LIF-receptor complex, LIF-R and gp130, during early mouse embryogenesis. These mRNAs were undetectable in 1- or 2-cell embryos, but all were present by the blastocyst stage. LIF transcripts were localised in the differentiated trophectoderm, and were absent from the pluripotential inner cell mass. In contrast, LIF-R mRNA was found in the inner cell mass but not in the trophectoderm. This complementary pattern of expression is suggestive of a paracrine coupling between stem cells and differentiated progeny at the earliest stage of mammalian development. After implantation, transcripts for all components were down-regulated in the embryo. High levels of LIF-R and gp130 mRNAs were observed in the deciduum, however. These dynamic, tissue-specific expression patterns are consistent with regulatory roles for LIF or related cytokines, both in the maintenance of pluripotency in the mouse embryo, and in development of the foeto-maternal interface.

Animals↗
PubMed1996

Roles of gp130 signaling pathways in cardiac myocytes: recent advances and implications for cardiovascular disease.

As we have discussed here, investigation of signaling pathways through gp130 to the nucleus in cardiac myocytes should uncover novel mechanisms of cardiac muscle growth and development. The dysregulation of this function caused by altered expression and/or altered function of gp130 may lead to pathological changes in cardiac myocytes. This is supported by findings in gp130 null mutants and the gp130-activated mouse model.

Animals↗
PubMed1996

Interleukin-6 inhibits the chemotaxis of human malignant plasma cell lines.

The chemotaxis of human malignant plasma cells is promoted by two extracellular matrix proteins (ECMs): fibronectin (FN) and laminin (LN). We examined the effect of the supernatant from a bone marrow stroma cell line, KM-101, on the chemotaxis of human malignant plasma cell lines to assess the chemotaxis-regulatory roles of the bone marrow microenvironment. Five human malignant plasma cell lines, FR4ds, OPM-1ds, U266/B1, RPMI-8226 and ARH-77 showed different profiles of the expression of beta 1 integrins of FN and LN receptors. FR4ds, OPM-1ds and U266/B1 cells showed chemotaxis promoted by FN (ChFN) and LN (ChLN). ARH-77 cells showed ChFN but not ChLN. RPMI-8226 cells did not show either ChFN or ChLN. The supernatant from KM-101 cells inhibited the chemotaxis of each of these cell lines regardless of whether the chemotaxis was promoted by FN or LN. Among the cytokines produced by KM-101 cells, it was postulated that IL-6 mediated this inhibitory effect because anti-IL-6 monoclonal antibody (MoAb) and anti-IL-6 receptor MoAb significantly reversed the inhibition. Recombinant IL-6 (rIL-6) also exhibited a similar inhibitory effect. Because anti-gp130 MoAb significantly reversed the chemotaxis inhibitory effect of rIL-6, the inhibitory signal is probably transduced via the signal transducing receptor component, gp130. The chemotaxis-regulatory effect is another previously unrecognized function of this pleiotropic cytokine, IL-6. High levels of IL-6 in the bone marrow microenvironment of patients with multiple myeloma appears to be favourable for the localization of myeloma cells there.

Antigens, CD↗
PubMed1996

Gp130, a shared signal transducing receptor component for hematopoietic and neuropoietic cytokines.

Most of the receptors for soluble factors functioning in the hematopoietic system belong to the class I cytokine receptor family. These receptors often share common signal transducing receptor components in the same family, which explains the functional redundancy of cytokines. One typical example is a group of receptor systems for interleukin-6 (IL-6) and related cytokines that share gp130 as a signal transducer. This subset of cytokines, i.e., IL-6, IL-11, leukemia inhibitory factor, oncostatin M, ciliary neurotrophic factor, and cardiotrophin-1, are all pleiotropic, exhibiting overlapping biological activities, and are known to function also in the neuronal system. In their receptor complexes, gp130 and ligand-specific chains possess no intrinsic tyrosine kinase domain but are associated with members of the Jak family of cytoplasmic tyrosine kinases. The Jak kinases become activated after ligand-induced homo- or heterodimerization of gp130. This activation appears to link the cell surface receptors to the nuclear genes through a series of biochemical changes, including tyrosine phosphorylation and activation of a latent cytoplasmic transcription factor called signal transducer and activator of transcription 3 (STAT3).

Antigens, CD↗
PubMed1996

The soluble form of the IL-6 receptor (sIL-6R alpha) is a potent growth factor for AIDS-associated Kaposi's sarcoma (KS) cells; the soluble form of gp130 is antagonistic for sIL-6R alpha-induced AIDS-KS cell growth.

Kaposi's sarcoma (KS) is most frequently associated with HIV-infected individuals (AIDS-KS). While AIDS-KS-derived spindle cells (AIDS-KS cells) contribute to the development of KS lesions, growth regulation of these cells in vivo is poorly understood. AIDS-KS cells express considerable amounts of the signal transducing subunit (gp130) of the IL-6 receptor, but only a scanty amount of its binding subunit (IL-6R alpha). This phenotype can account for the lack of IL-6 responsiveness of AIDS-KS cells. We now report that the soluble form of IL-6R alpha (sIL-6R alpha), lacking transmembrane and cytoplasmic regions, functions as a potent growth factor for AIDS-KS cells by making these cells responsive to IL-6. After exposure to sIL-6R alpha together with IL-6 in culture, AIDS-KS cells assumed a spindle-shaped morphology and showed a remarkable augmentation of growth, while IL-6 alone did not induce AIDS-KS cell growth. Even without the addition of IL-6, sIL-6R alpha induced significant growth levels of AIDS-KS cells. Since AIDS-KS cells express high levels of IL-6, it is likely that, in the presence of sIL-6R alpha, these cells acquire an IL-6 autocrine growth loop. Anti-gp130 antibodies blocked the action of sIL-6R alpha on AIDS-KS cells; hence, we refer to sIL-6R alpha as a gp130-related AIDS-KS cell growth factor. In contrast, the soluble form of gp130 (sgp130) had inhibitory effects on AIDS-KS cell growth, thereby suggesting that a complex regulatory system is involved in the modulation of the gp130-mediated AIDS-KS cell growth. In recent years, soluble forms of IL-6R alpha and gp130 have been detected in the sera of healthy individuals and increased levels of sIL-6R alpha as well as IL-6 have been noted in the sera of HIV-infected patients. It seems reasonable to assume that perturbed production of sIL-6R alpha and sgp130 may play a crucial role in the development and regression of AIDS-KS lesions by directly acting on growth of KS cells through the gp130-mediated pathway.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Characteristic localization of gp130 (the signal-transducing receptor component used in common for IL-6/IL-11/CNTF/LIF/OSM) in the rat brain.

The localization of gp130, the signal transducing receptor component used in common for interleukin (IL)-6, IL-11, ciliary neurotrophic factor (CNTF), LIF and OSM, in the rat brain was demonstrated by immunohistochemistry using an antibody specific to gp130. The gp130 immunoreactivity was observed in both glial and neuronal cells. Two distinct neuronal staining patterns were observed. The first showed neuropil staining, observed mainly in telencephalic structures including the hippocampus, cerebral cortex and caudate-putamen. The second pattern was observed on the cytoplasmic membrane of neuronal somata and was found primarily in the lower brainstem, in the large neurons of the reticular formation, and in spinal and cranial motor neurons. Electron-microscopic analysis revealed that both types of gp130 immunoreactivity were primarily associated with the cytoplasmic membrane and were not localized exactly at synaptic sites. Further, gp130 immunoreactivity was also observed in the oligodendrocytes and subependymal zone. These widespread but characteristic patterns of gp130 immunoreactivity overlap well with those of IL-6 receptor and CNTF alpha chains, suggesting a role of cytokines and growth factors such as IL-6 and CNTF via gp130 in certain specific regions of the brain.

Amino Acid Sequence↗
PubMed1996

Functional requirement of gp130-mediated signaling for growth and survival of mouse primordial germ cells in vitro and derivation of embryonic germ (EG) cells.

Leukemia inhibitory factor (LIF) is a cytokine known to influence proliferation and/or survival of mouse primordial germ cells (PGC) in culture. The receptor complex for LIF comprises LIF-binding subunit and non-binding signal transducer, gp130. The gp130 was originally identified as a signal-transducing subunit of interleukin (IL)-6 and later also found to be a functional component of receptor complexes for other LIF-related cytokines (oncostatin M [OSM], ciliary neurotrophic factor [CNTF] and IL-11). In this study, we have analyzed the functional role of gp130-mediated signaling in PGC growth in vitro. OSM was able to fully substitute for LIF; both cytokines promoted the proliferation of migratory PGC (mPGC) and enhanced the viability of postmigratory (colonizing) PGC (cPGC) when cultured on SI/SI4-m220 cells. Interestingly, IL-11 stimulated mPGC growth comparable to LIF and OSM, but did not affect cPGC survival. IL-6 and CNTF did not affect PGC. In addition, a combination of IL-6 and soluble IL-6 binding subunit (sIL-6R), which is known to activate intracellular signaling via gp130, fully reproduced the LIF action of PGC. Both in the presence and absence of LIF, addition of neutralizing antibody against gp130 in culture remarkably blocked cPGC survival. These results suggest a pivotal role of gp130 in PGC development, especially that it is indispensable for cPGC survival as comparable to the c-KIT-mediated action. We have further demonstrated that a combination of LIF with forskolin or retinoic acid, a potent mitogen for PGC, supported the proliferation of PGC, leading to propagation of the embryonic stem cell-like cells, termed embryonic germ (EG) cells. Since EG cells were also obtained by using OSM or the IL-6/sIL-6R complex in place of LIF, a significant contribution of gp130-mediated signaling in EG cell formation was further suggested.

Animals↗
PubMed1995

Interleukin (IL)-6 induction of osteoclast differentiation depends on IL-6 receptors expressed on osteoblastic cells but not on osteoclast progenitors.

We reported that interleukin (IL) 6 alone cannot induce osteoclast formation in cocultures of mouse bone marrow and osteoblastic cells, but soluble IL-6 receptor (IL-6R) strikingly triggered osteoclast formation induced by IL-6. In this study, we examined the mechanism of osteoclast formation by IL-6 and related cytokines through the interaction between osteoblastic cells and osteoclast progenitors. When dexamethasone was added to the cocultures, IL-6 could stimulate osteoclast formation without the help of soluble IL-6R. Osteoblastic cells expressed a very low level of IL-6R mRNA, whereas fresh mouse spleen and bone marrow cells, both of which are considered to be osteoclast progenitors, constitutively expressed relatively high levels of IL-6R mRNA. Treatment of osteoblastic cells with dexamethasone induced a marked increase in the expression of IL-6R mRNA. By immunoblotting with antiphosphotyrosine antibody, IL-6 did not tyrosine-phosphorylate a protein with a molecular mass of 130 kD in osteoblastic cells but did so in dexamethasone-pretreated osteoblastic cells. Osteoblastic cells from transgenic mice constitutively expressing human IL-6R could support osteoclast development in the presence of human IL-6 alone in cocultures with normal spleen cells. In contrast, osteoclast progenitors in spleen cells from transgenic mice overexpressing human IL-6R were not able to differentiate into osteoclasts in response to IL-6 in cocultures with normal osteoblastic cells. These results clearly indicate that the ability of IL-6 to induce osteoclast differentiation depends on signal transduction mediated by IL-6R expressed on osteoblastic cells but not on osteoclast progenitors.

Animals↗
PubMed1995

Regulation of mouse soluble interleukin-6 receptor secretion by decidua.

Regulation of msIL-6R secretion by mIL-6 and 8-bromo cAMP was examined using primarily cell culture of mouse decidua. Mouse decidua on day 11 of pregnancy was digested by collagenase and decidual cells were cultured for up to 3 days. Addition of mIL-6 and 8-bromo cAMP resulted in significant inhibition of msIL-6R secretion from cultured mouse decidual cells by the 2nd day in culture. The effects were dose-dependent and the lowest concentrations of mIL-6 and 8-bromo cAMP which cause significant inhibition of msIL-6R secretion were 250 pM and 50 microM, respectively. Northern blot analysis indicated that treatment of decidual cells with 8-bromo cAMP significantly decreased the steady-state level of mIL-6R mRNA. However, treatment of decidual cells with mIL-6 did not affect the steady-state level of mIL-6R mRNA. These results suggest that mIL-6 decreases msIL-6R secretion without changing of the steady-state level of mIL-6R mRNA, and that cAMP is one of the second messengers in mouse decidual cells involved in this down regulation of msIL-6R secretion.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1995

Continuous activation of gp130, a signal-transducing receptor component for interleukin 6-related cytokines, causes myocardial hypertrophy in mice.

To investigate the physiological roles of gp130 in detail and to determine the pathological consequence of abnormal activation of gp130, transgenic mice having continuously activated gp130 were created. This was carried out by mating mice from interleukin 6 (IL-6) and IL-6 receptor (IL-6R) transgenic lines. Offspring overexpressing both IL-6 and IL-6R showed constitutive tyrosine phosphorylation of gp130 and a downstream signaling molecule, acute phase response factor/signal transducer and activator of transcription 3. Surprisingly, the distinguishing feature of such offspring was hypertrophy of ventricular myocardium and consequent thickened ventricular walls of the heart, where gp130 is also expressed, in adulthood. Transgenic mice overexpressing either IL-6 or IL-6R alone did not show detectable myocardial abnormalities. Neonatal heart muscle cells from normal mice, when cultured in vitro, enlarged in response to a combination of IL-6 and a soluble form of IL-6R. The results suggest that activation of the gp130 signaling pathways leads to cardiac hypertrophy and that these signals might be involved in physiological regulation of myocardium.

Animals↗
PubMed1995

Cardiotrophin-1. Biological activities and binding to the leukemia inhibitory factor receptor/gp130 signaling complex.

Cardiotrophin-1 (CT-1) is a newly isolated cytokine that was identified based on its ability to induce cardiac myocyte hypertrophy. It is a member of the family of cytokines that includes interleukins-6 and -11, leukemia inhibitory factor (LIF), ciliary neurotrophic factor, and oncostatin M. These cytokines induce a pleiotropic set of growth and differentiation activities via receptors that use a common signaling subunit, gp130. In this work we determine the activity of CT-1 in six in vitro biological assays and examine the composition of its cell surface receptor. We find that CT-1 is inactive in stimulating the growth of the hybridoma cell line, B9 and inhibits the growth of the mouse myeloid leukemia cell line, M1. CT-1 induces a phenotypic switch in rat sympathetic neurons and promotes the survival of rat dopaminergic and chick ciliary neurons. CT-1 also inhibits the differentiation of mouse embryonic stem cells. CT-1 and LIF cross-compete for binding to M1 cells, Kd [CT-1] approximately 0.7 nM, and this binding is inhibited by an anti-gp130 monoclonal antibody. Both ligands can be specifically cross-linked to a protein on M1 cells with the mobility of the LIF receptor (approximately 200 kDa). In addition, CT-1 binds directly to a purified, soluble form of the LIF receptor in solution (Kd approximately 2 nM). These data show that CT-1 has a wide range of hematopoietic, neuronal, and developmental activities and that it can act via the LIF receptor and the gp130 signaling subunit.

Amino Acid Sequence↗