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T Kaisho

Publications and source records attributed to T Kaisho.

At least 37 records · Page 2Linked to original sources
PubMed1999

IL-18-deficient mice are resistant to endotoxin-induced liver injury but highly susceptible to endotoxin shock.

IL-18 is an IL-1-related cytokine which shares biological functions with IL-12. These include the activation of NK cells, induction of IFN-gamma production and Th1 cell differentiation. In this study we analyzed the effect of IL-18 deficiency on lipopolysaccharide (LPS)-induced liver injury and endotoxin shock in Propionibacterium acnes-primed mice. P. acnes-primed IL-18-deficient (IL-18KO) mice showed resistance to LPS-induced liver injury. Unexpectedly, P. acnes-primed IL-18KO mice were highly susceptible to LPS-induced endotoxin shock. Serum level of tumor necrosis factor (TNF)-alpha were markedly elevated (approximately 10-fold higher) within 1.5 h after LPS challenge in IL-18KO mice as compared with wild-type mice. Anti-TNF-alpha antibody administration to IL-18KO mice was significantly protective against endotoxin-induced lethality. P. acnes-primed IL-18KO macrophages produced approximately 6-fold more TNF-alpha protein than did P. acnes-primed wild-type control macrophages. Taken together, these findings demonstrate that IL-18 is responsible for the progression of endotoxin-induced liver injury as well as down-regulation of endotoxin-induced TNF-alpha production in P. acnes-primed mice.

Animals↗
PubMed1998

Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice.

Stat3, a member of STAT, is activated by a variety of cytokines such as IL-6 family of cytokines, granulocyte CSF, epidermal growth factor, and leptin. A recent study with mice genetically deficient in the Stat3 gene has revealed its important role in the early embryogenesis. To assess the function of Stat3 in adult tissues, we disrupted the Stat3 gene specifically in T cells by conditional gene targeting using Cre-loxP system. In Stat3-deficient T cells, IL-6-induced proliferation was severely impaired. IL-6 did not enhance cell cycle progression, but prevented apoptosis of normal T cells. In contrast, IL-6 did not prevent apoptosis of Stat3-deficient T cells. Antiapoptotic protein, Bcl-2, was normally up-regulated in response to IL-6 even in Stat3-deficient T cells. These results demonstrate that Stat3 activation is involved in IL-6-dependent T cell proliferation through prevention of apoptosis independently of Bcl-2.

Amino Acid Sequence↗
PubMed1998

Defective IL-2-mediated IL-2 receptor alpha chain expression in Stat3-deficient T lymphocytes.

Stat3, a member of signal transducers and activators of transcription (STAT), is activated by a variety of cytokines. Recently, mice lacking Stat3 specifically in T cells have been generated and shown to be defective in IL-6-induced proliferation due to the impairment in IL-6-mediated prevention of apoptosis. In the present study, we show that Stat3-deficient T cells are partially defective in IL-2-induced proliferation. Stat3-deficient T cells show impaired IL-2-mediated IL-2 receptor (IL-2R) alpha chain expression. When Stat3-deficient T cells are stimulated with high-dose IL-2, these T cells express IL-2Ralpha and proliferate to similar extents as wild-type T cells. These demonstrate that Stat3 activation is required for efficient T cell proliferation by IL-2 through IL-2Ralpha induction. Taken together, these findings demonstrate that Stat3 activation in T cells is responsible for IL-2- and IL-6-induced proliferation through distinct mechanisms.

Animals↗
PubMed1997

The roles of gamma 1 heavy chain membrane expression and cytoplasmic tail in IgG1 responses.

In antibody responses, B cells switch from the expression of immunoglobulin (Ig) mu and delta heavy (H) chains to that of other Ig classes (alpha, gamma, or epsilon), each with a distinct effector function. Membrane-bound forms of alpha, gamma, and epsilon, but not mu and delta, have highly conserved cytoplasmic tails. Mutant mice unable to express membrane gamma1 H chains or producing tailless gamma1 H chains failed to generate efficient IgG1 responses and IgG1 memory. H chain membrane expression after class switching is thus required for these functions, and class switching equips the B cell antigen receptor with a regulatory cytoplasmic tail that naïve B cells lack.

Animals↗
PubMed1996

Pancreatic islet cells express BST-1, a CD38-like surface molecule having ADP-ribosyl cyclase activity.

Cyclic ADP-ribose (cADPR), a well-known stimulator of ca(2+) release from the intracellular Ca(2+) pool, has recently emerged as a potential regulator of insulin secretion in pancreatic beta cells. As recently described, BST-1 is a glycosyl-phosphatidylinositol (GPI)-anchored surface molecule that exhibits homology with CD38 and Aplysia ADP-ribosyl cyclase. Like CD38, BST-1 has both ADP-ribosyl cyclase and cADPR hydrolase activities. As a step toward elucidating the physiological role of cADPR in insulin secretion we examined whether BST-1 is expressed in pancreatic islet cells. Sensitive reverse transcription-polymerase chain reaction detected almost as abundant expression of BST-1 mRNA in pancreatic islets as CD38 mRNA. Immunohistochemical analyses utilizing mirror image sections revealed that BST-1 protein is expressed in a majority of the cells in pancreatic islets and that at least beta cells and, to an even greater extent, alpha cells express BST-1. These observations suggest the involvement of multiple enzymes in the regulation of cADPR concentrations in pancreatic islet cells.

ADP-ribosyl Cyclase↗
PubMed1996

Elevated levels of the soluble form of bone marrow stromal cell antigen 1 in the sera of patients with severe rheumatoid arthritis.

OBJECTIVE: Bone marrow stromal cell antigen 1 (BST-1) is a novel glycosyl phosphatidylinositol-anchored ectoenzyme, which is overexpressed on bone marrow stromal and synovial cell lines derived from patients with rheumatoid arthritis (RA). To investigate the pathophysiologic roles of BST-1 in RA, we established an enzyme-linked immunosorbent assay (ELISA) system to detect the soluble form of BST-1 (sBST-1) and examined levels of sBST-1 in the sera of RA patients. METHODS: Concentrations of sBST-1 in sera from healthy donors and from patients with RA, osteoarthritis, Sjögren's syndrome, and systemic lupus erythematosus were measured with the ELISA. RESULTS: In 7% of the RA patient samples (10 of 143), concentrations of serum sBST-1 were higher (approximately 30-50-fold) than in non-RA samples. Serum sBST-1 concentrations showed no correlation with age, C-reactive protein level, or rheumatoid factor level. All RA patients with high concentrations of serum sBST-1 had severe disease with involvement of several large joints. CONCLUSION: We believe the measurement of serum sBST-1 may have prognostic value, but further analysis is necessary to clarify the clinical significance of elevated sBST-1 in RA.

ADP-ribosyl Cyclase↗
PubMed1995

Triggering of the human interleukin-6 gene by interferon-gamma and tumor necrosis factor-alpha in monocytic cells involves cooperation between interferon regulatory factor-1, NF kappa B, and Sp1 transcription factors.

We investigated the molecular basis of the synergistic induction by interferon-gamma (IFN-gamma)/tumor necrosis factor-alpha (TNF-alpha) of human interleukin-6 (IL-6) gene in THP-1 monocytic cells, and compared it with the basis of this induction by lipopolysaccharide (LPS). Functional studies with IL-6 promoter demonstrated that three regions are the targets of the IFN-gamma and/or TNF-alpha action, whereas only one of these regions seemed to be implicated in LPS activation. The three regions concerned are: 1) a region between -73 and -36, which is the minimal element inducible by LPS or TNF-alpha; 2) an element located between -181 and -73, which appeared to regulate the response to IFN-gamma and TNF-alpha negatively; and 3) a distal element upstream of -224, which was inducible by IFN-gamma alone. LPS signaling was found to involve NF kappa B activation by the p50/p65 heterodimers. Synergistic induction of the IL-6 gene by IFN-gamma and TNF-alpha, in monocytic cells, involved cooperation between the IRF-1 and NF kappa B p65 homodimers with concomitant removal of the negative effect of the retinoblastoma control element present in the IL-6 promoter. This removal occurred by activation of the constitutive Sp1 factor, whose increased binding activity and phosphorylation were mediated by IFN-gamma.

Base Sequence↗
PubMed1995

Activation of B lymphocyte maturation by a human follicular dendritic cell line, FDC-1.

Previously, we described the characteristics of a cell line that is derived from a low density fraction of human tonsillar cells and, on the basis of a number of criteria, is related to follicular dendritic cells (FDC). This line, FDC-1, binds B lymphocytes and not T lymphocytes, and promotes anti-Ig- or anti-CD40-induced B cell proliferation. In this work, we show that culturing B cells with small numbers of FDC-1 cells leads to significant production of IL-6 and of both IgM and IgG. As few as 50 to 100 FDC-1 augmented B cell IgM production by 10- to 100-fold. Although fixed FDC-1 cells, unlike live FDC-1 cells, do not stimulate Ig production, cell contact is not required for all FDC-dependent Ig production. Supernatants from cultured FDC-1 cells can also stimulate B cells to produce IgM, suggesting that FDC produce a soluble B cell stimulating factor(s). Augmentation of FDC-dependent IgM production by either IL-6 or IL-7 and augmentation of FDC-dependent IgG production by IL-4 does require FDC-1 cells to be in contact with B cells. When the effects of FDC-1 cells were compared with those of epithelial cell lines and human foreskin fibroblasts (HFF), both FDC-1 cells and HFF induced B cells to produce IgM. FDC-1, unlike HFF, were positive for CD40, CD54, CD73, CD74, and nerve growth factor receptor (NGFR), and unlike HFF, but like certain stromal cells, FDC-1 cells also expressed smooth muscle actin, and a novel marker for stromal cells, BST-1. The possible relationship of FDC-1 cells and FDC in general to a fibroblast/stromal cell lineage is discussed.

B-Lymphocytes↗
PubMed1995

Molecular cloning and chromosomal mapping of a bone marrow stromal cell surface gene, BST2, that may be involved in pre-B-cell growth.

Bone marrow stromal cells regulate B-cell growth and development through their surface molecules and cytokines. In this study, we generated a mAb, RS38, that recognized a novel human membrane protein, BST-2, expressed on bone marrow stromal cell lines and synovial cell lines. We cloned a cDNA encoding BST-2 from a rheumatoid arthritis-derived synovial cell line. BST-2 is a 30- to 36-kDa type II transmembrane protein, consisting of 180 amino acids. The BST-2 gene (HGMW-approved symbol BST2) is located on chromosome 19p13.2. BST-2 is expressed not only on certain bone marrow stromal cell lines but also on various normal tissues, although its expression pattern is different from that of another bone marrow stromal cell surface molecule, BST-1. BST-2 surface expression on fibroblast cell lines facilitated the stromal cell-dependent growth of a murine bone marrow-derived pre-B-cell line, DW34. The results suggest that BST-2 may be involved in pre-B-cell growth.

Amino Acid Sequence↗
PubMed1994

ADP ribosyl cyclase activity of a novel bone marrow stromal cell surface molecule, BST-1.

Human BST-1, a bone marrow stromal cell surface molecule, is a GPI-anchored protein that facilitates the growth of pre-B cells. The deduced amino acid sequences of human and mouse BST-1 show around 30% homology with those of CD38 and Aplysia ADP ribosyl cyclase. Therefore, like CD38, BST-1 might possess ADP ribosyl cyclase activity. Here, we report the establishment of a stable transformant CHO cell line, which secretes truncated human soluble BST-1, and show that purified soluble BST-1 displays both ADP ribosyl cyclase and cADPR hydrolase activities.

ADP-ribosyl Cyclase↗
PubMed1994

Molecular cloning of murine BST-1 having homology with CD38 and Aplysia ADP-ribosyl cyclase.

Human BST-1, a bone marrow stromal cell surface antigen, is a glycosyl-phosphatidylinositol-anchored protein that facilitates the growth of pre-B cells. We report here the molecular cloning of murine BST-1 cDNA. The deduced amino acid sequence of murine BST-1 had 71% similarity with human BST-1 and 30 and 25% similarity with CD38 and Aplysia adenosine diphosphate-ribosyl cyclase, respectively. Murine BST-1 mRNA was expressed in the bone marrow, spleen and thymus in lymphoid organs, and the lung, kidney and heart in non-lymphoid organs. Restriction fragment length polymorphism (RFLP) was shown in BALB/c, DBA/2 and NZB vs C57BL/6, A/J, CBA/N, NZW, BXSB and MRL/lpr. RFLP was mapped to the 5' portion of the murine BST-1 gene.

3T3 Cells↗
PubMed1994

BST-1, a surface molecule of bone marrow stromal cell lines that facilitates pre-B-cell growth.

Bone marrow stromal cells are essential for B-lymphocyte development. However, how stromal cells regulate B lymphopoiesis is not clear. In this paper, we report the molecular cloning of a stromal cell line-derived glycosyl-phosphatidylinositol-anchored molecule, BST-1, that facilitates pre-B-cell growth. The deduced amino acid sequence of BST-1 exhibited 33% identity with CD38. BST-1 was expressed in a wide range of tissues and in umbilical vein endothelial cells, whereas it was scarcely expressed in a variety of hematopoietic cell lines. The gene for BST-1 was assigned to chromosome 14q32.3, where immunoglobulin heavy-chain genes are clustered. BST-1 expression was enhanced in rheumatoid arthritis patient-derived bone marrow stromal cell lines that were previously shown to have an enhanced ability to support the growth of a pre-B-cell line as compared with stromal cell lines derived from healthy donors.

ADP-ribosyl Cyclase↗
PubMed1994

Generation and characterization of a monoclonal antibody that inhibits stromal cell-dependent B lymphopoiesis.

We generated a mAb, R4, against a stromal cell line, ST2, which is one of several stromal cell lines that can support in vitro B lymphopoiesis. Flow cytometry studies using R4 revealed that R4 reacted with several stromal, fibroblast, and some B cell lines, but not with freshly isolated bone marrow cells, splenocytes, thymocytes, or T cell lines. R4 could immunoprecipitate a M(r) = 24-kDa protein (p24) and a M(r) = 55-kDa protein (p55) from a stromal cell line and a B cell line, respectively. R4 inhibited the development of B cell progenitors from bone marrow cells in cultures supported by stromal cell lines, ST2, or op/op fibroblast line, but did not inhibit myelopoiesis supported by ST2. R4 also inhibited the growth of a stromal cell-dependent pre-B cell line, DW8, but not of two stromal cell-independent B cell lines, 70Z/3 and M12, despite the fact that R4 reacted all three of these lines. Because R4 inhibited B lymphopoiesis in the transwell culture where stromal cells are not allowed to contact pre-B cells, R4 Ag may not directly affect cellular contact. In vivo treatment of pregnant mice with R4 caused a reduction in the number of B cell progenitors in the bone marrows of some of the newborn offspring.

Animals↗
PubMed1993

Ionizing radiation induces expression of interleukin 6 by human fibroblasts involving activation of nuclear factor-kappa B.

We here report that human lung fibroblasts respond to x-ray treatment (XRT) with release of interleukin (IL)-6. Synthesis of IL-6 upon ionizing radiation is preceded by an increase of IL-6 transcript levels resulting from transcriptional activation of the IL-6 gene. Analysis of deleted fragments of the IL-6 promoter indicated that transcriptional activation of the IL-6 promoter was due to enhanced binding activity of the transcription factor nuclear factor (NF)-kappa B. Although AP-1 did not participate in the rapid induction of the IL-6 promoter, its binding activity was also enhanced by XRT. In contrast to binding kinetics observed with NF-kappa B, AP-1 binding following XRT was biphasic with the second peak being dependent on de novo protein synthesis. In contrast, however, NF-IL-6 activity was not enhanced by XRT in fibroblasts. The introduction of both the NF-kappa B- and the AP-1 recognition sequence conferred inducibility by XRT to a heterologous promoter, with reporter gene activity being maximal 24 or 48 h following XRT, respectively. Sequential activation of two distinct transcription factors might thus contribute to synchronize transcriptional activation of different genes participating in the x-ray response.

Base Sequence↗
PubMed1993

Transcriptional activation of the interleukin-6 gene by HTLV-1 p40tax through an NF-kappa B-like binding site.

The interleukin-6 (IL-6) gene is expressed by various stimuli including cytokines or viral infections, such as human T-cell leukemia virus type I (HTLV-1). However, it has not been well established how HTLV-1 induces the expression of the IL-6 gene. In the present study, we demonstrated that HTLV-1-derived transactivator protein, p40tax, could stimulate endogenous IL-6 gene expression. Furthermore, we showed that the NF-kappa B binding site (IL-6 kappa B site) located between -74 and -62 upstream of the cap site of the IL-6 gene was an essential cis-acting element for p40tax-mediated transactivation of the IL-6 gene expression by utilizing a series of 5' deletion mutants of the IL-6 5' flanking region as well as a construct with a mutated IL-6 kappa B site. We identified the presence of two nuclear factor complexes that bound to the IL-6 kappa B site. One was constitutively expressed, and the other was inducible by p40tax. Taken together, HTLV-1 p40tax directly induces IL-6 gene expression through the IL-6 kappa B site, indicating the close association between IL-6 overproduction and HTLV-1 infection.

Base Sequence↗
PubMed1992

Human bone marrow stromal cell lines from myeloma and rheumatoid arthritis that can support murine pre-B cell growth.

In order to elucidate the pathologic significance of the bone marrow (BM) microenvironment in multiple myeloma (MM) and rheumatoid arthritis (RA), we established patient- or healthy donor (HD)-derived BM stromal cell lines by transfecting the plasmid for expression of SV40 large T Ag and examined their ability to support the stromal cell-dependent growth of a pre-B cell line, DW34. The means of recovered cell numbers of DW34 co-cultured with MM- and RA-derived BM stromal cell lines ranged from 6- to 10-fold more than those with HD-derived ones. Their enhanced ability to support DW34 cell growth was not caused by cytokines, including IL-6, IL-7, and c-kit ligand, although exogenous IL-7 could augment the growth-supporting ability. DW34 cell growth on the stromal cell lines was abolished by inhibiting cell-to-cell interaction with a membrane filter. FACS analysis revealed that the stromal cell lines did not express LFA-1 alpha, beta, NCAM, or ELAM-1. Both patient and HD BM stromal cell lines variably expressed ICAM-1, VCAM-1, and CD44. However, surface expression levels of these molecules did not correlate with the ability of the stromal cell lines to support DW34 cell growth. Taken together, these results suggested that BM microenvironment might play important roles in the pathogenesis of MM and RA.

Animals↗
PubMed1992

Retinoic acid inhibits interleukin-6-induced macrophage differentiation and apoptosis in a murine hematopoietic cell line, Y6.

We established a radiation-induced murine hematopoietic cell line, Y6, that could be induced to differentiate into macrophages by interleukin-6 (IL-6). IL-6 also induced growth inhibition and apoptosis in Y6 cells. Retinoic acid (RA) inhibited such effects of IL-6 on Y6 cells. The inhibitory effect of RA on the effects of IL-6 was not caused by the downregulation of the IL-6 receptor, because RA neither affected the expression of IL-6 receptor mRNA nor the expression of IL-6 receptor molecule on the cell surface. Furthermore, RA did not inhibit the IL-6-induced expression of junB mRNA, indicating that the expression of functionally active IL-6 receptor and the signal transduction pathway activating the junB gene are not inhibited by RA. IL-6-induced macrophage differentiation of Y6 cells was preceded by the downregulation of the c-myc gene, which was also prevented by RA. Because the inhibitory effect of RA on Y6 cells was reversible and seemed not to require de novo protein synthesis, the RA receptor by itself might be directly involved in the inhibition of the IL-6 signal transduction pathway. The results indicated that the IL-6 signal transduction pathways leading to the induction of macrophage differentiation and junB gene expression can be dissected by RA.

Animals↗