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T Kishimoto

Publications and source records attributed to T Kishimoto.

At least 343 records · Page 19Linked to original sources
PubMed1997

B cells regulate CD40 ligand-induced IL-12 production in antigen-presenting cells (APC) during T cell/APC interactions.

Although stimulation of freshly isolated murine spleen cells with anti-CD3 mAb or Con A failed to generate IL-12 production, the same cell preparations depleted of B cells produced IL-12. Addition of normal B cells inhibited IL-12 production in a cell number-dependent manner. IL-12 production was dependent on the presence of CD4+, but not of CD8+, T cells, and inhibited by addition of anti-CD40 ligand (CD40L) mAb. Anti-CD3 or Con A stimulation induced CD40L expression only on CD4+ T cells, which was inhibited in the presence of B cells. IL-12 production was also induced by interactions between CD40L-transfected Chinese hamster ovary cells and splenocytes depleted of T and B cells, but not of APC, indicating CD40L-induced IL-12 production by APC. The involvement of CD40 molecules was examined by comparing the ability of cells from CD40-deficient (CD40 -/-) and wild-type mice (CD40 +/+) to produce IL-12. Spleen cells from CD40 -/- and CD40 +/+ mice produced comparable amounts of IL-12 in response to bacterial stimuli. However, the B cell-depleted fraction from CD40 -/- mice failed to produce IL-12 when stimulated with anti-CD3 or Con A or when cocultured with CD40L-expressing Chinese hamster ovary cells. These results indicate that CD40L expressed on activated T cells induces APC to produce IL-12 through CD40/CD40L interaction, but this pathway is competitively inhibited by CD40+ B cells incapable of producing IL-12 upon stimulation with CD40L. Thus, this might represent a novel mechanism underlying the regulation of cell-mediated and humoral immunity.

Animals↗
PubMed1997

Lineage- and differentiation stage-specific expression of LSM-1 (LPAP), a possible substrate for CD45, in human hematopoietic cells.

CD45, a transmembrane tyrosine phosphatase, is found on almost all nucleated hematopoietic cells and plays a crucial role in lymphocyte activation and differentiation. We recently achieved isolation of the human LSM-1 (hLSM-1) gene, whose product is a possible substrate for CD45, and we raised antibodies against the hLSM-1 protein. hLSM-1 expression in hematopoietic cells was examined with Northern and Western blot, fluorescence-activated cell sorter, and immunocytochemical analyses. It was found that in the lymphoid lineage, T and B lymphocytes as well as NK cells expressed LSM-1, whereas terminally differentiated plasma cells did not. As for the myeloid lineage, immature myeloid cells expressed LSM-1, whereas terminally differentiated granulocytes and monocytes did not. In the erythroid lineage, normal erythroblasts expressed very low levels of LSM-1, while erythroid cell lines (K562 and HEL) did not. Megakaryocytes did not express LSM-1. Both CD34+/CD33- and CD34+/CD33+ hematopoietic progenitor cells weakly expressed LSM-1. These results showed that LSM-1 is expressed in a lineage- and differentiation stage-specific fashion.

Blotting, Western↗
PubMed1997

Interleukin-6 overexpression cannot generate serious disorders in severe combined immunodeficiency mice.

C57BL/6 human interleukin-6 (IL-6) transgenic mice develop mesangial proliferative glomerulonephritis with massive IgG1 plasmacytosis and die of renal failure in early life. To test whether the IL-6 overexpression could cause development of mesangial proliferative glomerulonephritis without plasmacytosis or promote proliferation of immature B cells that have not undergone immunoglobulin gene rearrangement, the IL-6 transgene was introduced into mice with severe combined immunodeficiency (SCID). In the immunocompetent littermate IL-6 transgenic mice, there were various symptoms such as plasmacytosis, nephropathy, anemia, and thrombocytosis, accompanied by marked increases in serum IL-6 levels as they aged. All these mice died by 25 weeks of age. In contrast, the SCID-IL-6 transgenic mice had no such abnormalities, except certain hematological changes, although the transgene was expressed in various tissues. In these mice, the serum IL-6 levels were 10- to 15-fold higher than those in the nontransgenic mice, and they remained constant throughout their lives. Furthermore, there were no signs of lymphoid development. This study demonstrates that deregulation of IL-6 expression does not stimulate cell growth or differentiation of immature B cells, and thus does not result in plasmacytosis and age-related increases in IL-6 production, and also does not generate mesangial proliferative glomerulonephritis.

Animals↗
PubMed1997

In vivo but not in vitro stimulations rescue of the defective class switching to IgG or IgA in B-cells of immunodeficiency with hyper IgM.

In an X-linked immunodeficiency with hyper IgM (X-HIM), several mutations of genes coding for CD40 ligand are responsible for B-cell defects. However, it is controversial whether the defective class switching from IgM to IgG or IgA but not IgE is rescued by in vitro stimulations or not. In six X-HIM patients, signaling through CD40 induced IgE but not IgG or IgA secretion in vitro. When transferred into SCID mice, however, B-cells of X-HIM patients secreted as much IgG and IgA as those of healthy controls. Moreover, sIgG and sIgA expressions were also induced by the in vivo stimulation. These results support that B-cells of X-HIM patients are defective of in vitro class switching from IgM to IgG or IgA and show that the in vivo stimulations rescue the defective class switching and suggest that the class switching of IgE and that of IgG or IgA might be regulated quite differently.

Animals↗
PubMed1997

Novel missense mutation in cardiac troponin T gene found in Japanese patient with hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy (HCM) is a primary cardiomyopathy with an autosomal dominant pattern of inheritance. The disease bearing genes for HCM in HCM families have been identified as beta-myosin heavy chain, alpha-tropomyosin, cardiac troponin T (cTnT) and myosin binding protein-C genes. In the present study, we searched for the mutations in the cTnT gene in Japanese HCM patients. Single-strand conformation polymorphism gel analysis of polymerase chain reaction-amplified product was used to search for the mutations in the exons 8, 9 and 15 of the cTnT gene from 60 familial HCM patients. Clinical studies of the family members were performed and the incidence of sudden or disease-related deaths within the family was also examined. We have identified a novel missense mutation in exon 9 (Ala104Val) of the cTnT gene in a patient with familial HCM. Because the missense mutation was found at the residue conserved through chicken to humans and was not detected in the more than 50 normal controls, it was suggested that this missense mutation is the cause of HCM in this family. Although the affected family members presented moderate hypertrophy of the left ventricular wall, they were symptomatic and there was a high incidence of sudden death in her family members. Among Japanese patients with familial HCM, a novel missense mutation (Ala104Val) in the cTnT gene was identified. Familial HCM is genetically heterogeneous in Japanese HCM patients as observed in Caucasian kindreds. The disease in the kindred was severe and there was a high incidence of sudden or disease-related deaths in the kindred with this mutation.

Adult↗
PubMed1997

In vivo regulation of the entry into M-phase: initial activation and nuclear translocation of cyclin B/Cdc2.

The cyclin B/Cdc2 complex, Cdc2 kinase governs M-phase. Although the intracomplex modification for its activation in vitro has been described extensively, its regulation in vivo is not so well explained so far. In this article, we will focus on the intracellular regulation of the cyclin B/Cdc2 activity, in particular, how it is initially activated in vivo, how its nuclear translocation is executed specifically at the onset of M-phase, and how the activation and the nuclear translocation are coordinated in the cell. These concerted regulations may determine the appropriate timing for the initiation of M-phase.

Animals↗
PubMed1997

STAT6: its role in interleukin 4-mediated biological functions.

Interleukin (IL) 4 is known to be a cytokine which plays a central role in the regulation of immune response. Studies on cytokine signal transduction have clarified the mechanism by which IL4 exerts its functions. Two cytoplasmic proteins, signal transducer and activator of transcription (STAT) 6 and IL4-induced phosphotyrosine substrate/insulin receptor substrate 2 (4PS/IRS2), are activated in IL4 signal transduction. Recent studies from STAT6-deficient mice have revealed the essential role of STAT6 in IL4-mediated biological actions. In addition, STAT6 has also been demonstrated to be important for the functions mediated by IL13, which is related to IL4. IL4 and IL13 have been shown to induce the production of IgE, which is a major mediator in an allergic response. These findings indicate that STAT6 activation is involved in IL4- and IL13-mediated disorders such as allergy.

Animals↗
PubMed1997

Demyelination in severe combined immunodeficient mice by intracisternal injection of cerebrospinal fluid cells from patients with multiple sclerosis: neuropathological investigation.

Demyelinating lesions have been observed in severe combined immunodeficient (SCID) mice after intracisternal administration of cerebrospinal fluid cells (CSFC) from patients with multiple sclerosis (MS). Further investigation in our laboratory revealed that CSFC from 6 to 15 patients at exacerbation of MS caused demyelination. The factor leading to demyelination appears to be the high frequency of relapses during a short period, but not to the severity of the disease. Neuropathological and immunohistochemical studies revealed that a lack of inflammatory mononuclear cell infiltration within and around the demyelinating lesions or in leptomeninges was a common characteristic in all SCID mice with CSFC-induced demyelination. In affected mice killed 2-3 weeks after intracisternal administration of CSFC, foamy/vacuolar lesions with a small or moderate number of lipid-laden macrophages were seen in the white matter. Ultrastructurally, relative preservation of axons, in contrast to myelinoclastic features, as well as some remyelinated axons were observed. In affected SCID mice killed 4-6 weeks after intracisternal administration, more widespread foamy macrophages and necrotic foci with poor remyelination were seen. The findings were similar to those seen in experimental allergic encephalomyelitis, though without lymphocytic infiltration, but were quite different from the lesions observed in Theiler's murine encephalitis virus infection. The absence of an immunohistochemical reaction to the human leukocyte common antigen in the infiltrating mononuclear cells suggested that the graft-versus-host reaction was unlikely cause of the demyelinating lesions.

Adolescent↗
PubMed1997

Myeloma biology and therapy. Present status and future developments.

Recent progress in cytokine studies has made it possible to understand the pathophysiological roles of cytokines in multiple myeloma. Specifically, interleukin (IL)-6 is a potent growth factor for myeloma cells and is also responsible for the progressive bone resorption characteristic of this disease. On the basis of this evidence, clinical trials to interfere with IL-6 signals have been initiated for the treatment of patients with advanced myeloma. Such a new therapeutic approach as well as myeloblative therapy should be able to provide us with the breakthrough needed to prevail over this so far incurable disease.

Antigens, CD↗
PubMed1997

Characterization of mechanisms of interleukin-6 gene repression by estrogen receptor.

Estrogens are the most effective agents available for preventing osteoporosis, and their principal role in bone metabolism is the inhibition of interleukin-6 (IL-6) production in osteoblasts and bone marrow stromal cells. We examined the mechanism of inhibitory effect of estrogens on the 190 bp proximal promoter of the IL-6 gene. Promoter activity induced by transfection of both NF-kappaB p65 subunit and NF-IL6 was decreased by 45% by estradiol (E2)-estrogen receptor (ER) complexes. The inhibitory effect of E2 was also observed on a mutant IL-6 promoter in which the NF-IL6 binding site was disrupted. E2 repressed the wild-type promoter activity induced by NF-kappaB p65 subunit alone, but had no effect on that induced by NF-IL6 alone. These findings suggested that estrogens inhibit IL-6 production by interfering with the function of NF-kappaB rather than that of NF-IL6. The ER mutant, HE19, which does not contain the A/B domain, repressed the induction by NF-kappaB to the same extent as wild-type ER HE0, whereas the effect of C-terminal deletion mutant, HE21, was only marginal. The antiestrogen, 4-hydroxytamoxifen (OHT), had no effect on IL-6 promoter activity, suggesting that E2-induced conformational change of the hormone binding domain plays an important role in protein-protein interaction between ER and NF-kappaB. E2 had no effect on the nuclear translocation of NF-kappaB, and electrophoretic mobility shift assay showed that the presence of E2-ER complexes did not affect the ability of NF-kappaB to bind to specific DNA sequences.

Animals↗
PubMed1997

Interleukin-6 secreting phaeochromocytoma associated with clinical markers of inflammation.

Phaeochromocytomas have been shown to produce not only catecholamines but other neuropeptides and hormones, with a variety of clinical manifestations. We report a 70-year-old female patient with phaeochromocytoma exhibiting sustained hypertension, low-grade fever, thrombocytosis, and elevated levels of plasma fibrinogen and C-reactive protein. Serum interleukin (IL)-6 levels were significantly elevated, whereas serum IL-1 alpha and IL-1 beta were not detectable. After surgical removal of the tumour, hypertension and low-grade fever disappeared, and the laboratory finding including serum IL-6 concentrations became normal. Immunohistochemical study of the tumour showed positive staining for IL-6. Culture of the resected tumour revealed the production of large amounts of IL-6. It is suggested that IL-6 secreted by the tumour was responsible for some of the clinical manifestations in this patient.

Adrenal Gland Neoplasms↗
PubMed1997

Gastrointestinal hepatoid adenocarcinoma: venous permeation and mimicry of hepatocellular carcinoma, a report of four cases.

AIMS: Four cases of hepatoid adenocarcinoma, three in the stomach, and one in the sigmoid colon, are presented to emphasize venous permeation and mimicry of hepatocellular carcinoma by metastatic liver nodules. METHODS AND RESULTS: Tumour cells in all cases extensively invaded vems, and intravenous tumour thrombi in two cases were grossly observed as anastomosing, worm-like cords up to 10 mm in diameter in the lesser omentum and mesentery in continuity with the primary mucosal lesions. The cytological features and trabecular architecture of the metastatic liver nodules in these subjects mimicked primary hepatocellular carcinoma. In a third case the tumour contained grossly visible bile in a metastatic lung nodule, but there was no evidence of bile production in the primary gastric or metastatic liver lesions. In the fourth case, detailed histopathological study revealed a gastric origin of the hepatoid adenocarcinoma, rather than primary hepatocellular carcinoma metastatic to the stomach, the initial diagnosis. CONCLUSIONS: These cases are reported here to draw attention to this rare variant of gastrointestinal adenocarcinoma, its mimicry of hepatocellular carcinoma when metastatic to the liver and other sites, and its propensity for venous permeation.

Adenocarcinoma↗
PubMed1997

Demonstration of an E-box and its CNS-related binding factors for transcriptional regulation of the mouse type 1 inositol 1,4,5-trisphosphate receptor gene.

The type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) is expressed abundantly in the CNS, such as in cerebellar Purkinje cells and the hippocampus. We established a tissue-specific cell-free transcription system and studied regulatory properties of the 5' upstream region of the IP3R1 gene by use of this system. Deletion analyses of the promoter revealed several cis elements that function significantly in brain nuclear extracts. Among those elements, sequences from -398 to -295 showed the most predominant cerebellum-specific positive function. Footprint analyses demonstrated a factor-binding region from -334 to -318, termed box-I, that contained an E-box consensus sequence. Electrophoretic mobility shift assay revealed CNS-related basic helix-loop-helix proteins for the box-I. Mutational studies using the function assay and competitive electrophoretic mobility shift assays demonstrated a good correlation between the box-I-binding factors and the activated transcription. Box-I-binding factors were present abundantly in adult mouse CNS, whereas their existence was restricted in embryonic and nonneural tissues. Transient chloramphenicol acetyltransferase assay for the IP3R1 promoter revealed the requirement of box-I in Neuro2a neuroblastoma cells. In the postnatal CNS, multiple basic helix-loop-helix factors are expressed abundantly, some of which are suggested to activate IP3R1 gene expression in the mammalian CNS.

Animals↗
PubMed1997

Role of the pyrrolidine ring of proline in determining the substrate specificity of cdc2 kinase or cdk5.

To examine structural features of proline which are essential for the proline-directed phosphorylation by cdc2 kinase or cdk5, we prepared the peptide representing the cdc2 kinase phosphorylation site at Ser-55 in vimentin [Ser-Leu-Tyr-Ser-Ser-Ser55-Pro56-Gly-Gly58-Ala-Tyr-NH2], the peptide containing arginine in place of Gly-58, and their derivatives containing various N-methylamino acids or proline homologs in place of Pro-56, and tested them as substrates for the kinases. While substitution of the proline by proline homologs (L-pipecolic acid or L-azetidine-2-carboxylic acid) increased the K(m) value 2- to 4-fold at utmost, substitution by N-methylamino acids (sarcosine, L-N-methylalanine, L-N-methylvaline, or L-N-methylleucine) increased the K(m) value 7- to 40-fold for cdc2 kinase. For cdk5, these substitutions led to parallel effects on the K(m) value to those found for cdc2 kinase; cdk5 recognized the peptides with a proline specificity similar to that for cdc2 kinase. These results suggest that the pyrrolidine ring of proline is important for substrate recognition by cdc2 kinase or cdk5. Molecular dynamics and molecular mechanics simulations indicated that the pyrrolidine ring of proline is optimal to stabilize a beta-turn at the phosphorylation site and that the K(m) values of the peptides for the enzymes might be related to the probability of the turn structure. The results obtained here also suggest that the pyrrolidine ring of proline is required to maintain a high V(max) value for cdc2 kinase or especially for cdk5. These will aid in designing specific substrates or inhibitors for cdc2 kinase or cdk5.

CDC2 Protein Kinase↗
PubMed1997

Inhibitory effects of the antiangiogenic agent TNP-470 on establishment and growth of hematogenous metastasis of human pancreatic carcinoma in SCID beige mice in vivo.

Effects on the liver of the antiangiogenesis agent O-(chloroacetyl-carbamoyl) fumagillol (TNP-470) on hematogenous metastasis of a human pancreatic carcinoma cell line were examined. One million PCI-43 cells, a human pancreas carcinoma cell line, were injected into the spleen of SCID beige mice, then TNP-470 at 30 mg/kg was administered subcutaneously every other day. The mice were killed 6 or 10 weeks thereafter and metastatic nodules in the liver were counted and measured microscopically. Metastases were inhibited and an approximately 10% loss of weight was evident in the TNP-470-administered mice. There was no suppression in maximal size of metastatic colonies in mice given the agent for 6 weeks, while inhibition was apparent in mice given the drug for 10 weeks. Suppression of proliferation and an increase in apoptosis were evident in metastatic nodules in the TNP-470-administered groups, following stainings for proliferative cell nuclear antigen and terminal deoxytransferase-mediated dUTP-biotin nick end-labeling, respectively. TNP-470 inhibited the proliferation of human umbilical vein endothelial cells but not PCI-43 in vitro. TNP-470 did not suppress production of vascular endothelial growth factor by PCI-43 cells. Neovascularization in vivo induced by PCI-43 cells was suppressed in the TNP-470-administered mice, using a diffusion chamber placed in subcutaneous tissues of SCID beige mice. These observations suggest that inhibition of angiogenesis is effective in suppressing establishment and subsequent growth of hematogenous micrometastases of pancreatic adenocarcinoma to the liver.

Animals↗
PubMed1997

Elevated soluble Fas/APO-1 (CD95) levels in silicosis patients without clinical symptoms of autoimmune diseases or malignant tumours.

Soluble Fas (sFas) is produced as translation products of alternative mRNA splicing, and antagonizes the membranous Fas molecule in Fas/Fas ligand interactions. We investigated the serum sFas levels in 64 Japanese silicosis patients with no clinical symptoms of autoimmune diseases or malignant tumours, using ELISA for sFas. The serum sFas levels in the silicosis patients were significantly higher than those in healthy volunteers. Elevated serum sFas levels were also detected in patients with systemic lupus erythematosus but, unexpectedly, no difference was observed in sFas levels between progressive systemic sclerosis patients and healthy volunteers. On the other hand, there was no significant difference in the expression of Fas on peripheral blood lymphocytes between the patients with silicosis and age-matched healthy volunteers. These observations provided the first evidence that serum sFas levels are elevated in silicosis patients without clinical symptoms of autoimmune diseases or malignant tumours. It remains to be clarified whether patients with elevated sFas levels have a tendency to develop autoimmune diseases later, or whether some other distinct factor(s) is necessary to initiate the progression of autoimmune diseases.

Aged↗