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T Kishimoto

Publications and source records attributed to T Kishimoto.

At least 55 records · Page 3Linked to original sources
PubMed2001

Autoantibodies detectable in the sera of silicosis patients. The relationship between the anti-topoisomerase I antibody response and HLA-DQB1*0402 allele in Japanese silicosis patients.

Eighty-one Japanese silicosis patients and 66 healthy volunteers were analyzed for autoantibodies by ELISA, and HLA-genotyping using the PCR-RFLP method was performed. Anti-topoisomerase I (anti-topo I) autoantibodies were detected in seven patients without any clinical features of autoimmune diseases such as progressive systemic sclerosis (PSS), although anti-topo I have been mostly reported in PSS patients. Antibodies directed to RNP, ssDNA, dsDNA and cent-B were not detected among the anti-topo I positive patients. The indirect immunofluorescent staining pattern of Hep-2 cells with the sera of anti-topo I positive silicosis patients demonstrated the typical mode of anti-topo I autoantibodies observed in the patients with PSS. The allelic frequency of HLA-DQB1*0402 was significantly higher in anti-topo I positive patients (28.6%) than in anti-topo I negative patients (1.5%, P < 0.001) or healthy controls (0.8%, P<0.001). HLA-DQB1*0301, DQB1*0601 and DPB1*1801 alleles were more frequently detected in anti-topo I positive patients than in the patients without anti-topo I or in healthy volunteers, but no significant difference was observed. DQB1 allele is associated with the induction of anti-topo I autoantibodies in Japanese silicosis patients, but the allele is not the same as in Caucasian PSS patients. Another allele (DQB1*0402) plays an important role in Japanese silicosis patients. The most important factor to induce anti-topo I autoantibodies seems not to be the type of alleles themselves, but the position of some specific amino acid residues in the DQ beta first domain. These findings will be useful for preventing occupational autoimmune diseases.

Aged↗
PubMed2001

Enhancement of T helper2 response in the absence of interleukin (IL-)6; an inhibition of IL-4-mediated T helper2 cell differentiation by IL-6.

Functional roles of interleukin (IL-)6 in T cell response were investigated. Mice deficient in IL-6 and wild mice were immunized with antigens (myelin oligodendrocyte glycoprotein or methylated BSA) and production of IL-4 and interferon (IFN)-gamma by regional lymph nodes was measured. IL-6 deficiency led to an enhancement of IL-4 and an inhibition of IFN-gamma production. Moreover, polyclonal stimulation of spleen T cells from unimmunized IL-6-deficient mice with anti-CD3 plus anti-CD28 antibodies (Abs) demonstrated an enhancement of T helper (Th)(2)responses. The presence of IL-6, however, augmented IL-4 production but it inhibited IFN-gamma expression by spleen T cells in response to polyclonal stimulation and by antigen-primed spleen T cells in response to re-challenge with the antigen. In contrast, the induction of spleen CD4-positive T cells into Th(2)cells in vitro by the anti-CD3 plus IL-4 was completely suppressed by exogenously added IL-6, whereas Th(1)differentiation of T cells by the anti-CD3 plus IL-12 was not inhibited by the presence of IL-6. Thus, these results indicate that IL-6 physiologically could modulate qualitative T cell response and suggest that it augments Th(1)responses partly through its inhibitory capability of IL-4-induced Th(2)differentiation of naive T cells.

Adjuvants, Immunologic↗
PubMed2001

BLNK mediates Syk-dependent Btk activation.

Btk is a critical molecule in B cell antigen receptor (BCR)-coupled signaling, and its activity is regulated by Lyn and Syk. Although the molecular mechanism of Lyn-dependent Btk activation has been investigated, that of Syk-dependent Btk activation has remained unidentified. We have demonstrated that BLNK mediates Syk-dependent Btk activation. In a reconstitution cell system, coexpression of BLNK allows Syk to phosphorylate Btk on its tyrosine 551, leading to the enhancement of Btk activity. This phosphorylation depends on the interaction of Btk and BLNK by means of the Btk-Src homology 2 domain. The existence of such an activation mechanism is supported by the observation that the BCR-induced Btk phosphorylation and activation are significantly reduced in BLNK-deficient B cells as well as in Syk-deficient B cells. Although previous observations have identified the function of BLNK as the linker that integrates the action of Btk and Syk into downstream effectors such as phospholipase Cgamma2, our present study indicates another function of BLNK that connects the activity of Syk to that of Btk.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Severely reduced production of klotho in human chronic renal failure kidney.

We recently identified a novel gene, termed klotho (kl) that is involved in the development of a syndrome in mice resembling human aging. A defect of the kl gene expression in mice leads to multiple disorders including arteriosclerosis, osteoporosis, ectopic calcification, and skin atrophy together with short life-span and infertility. Patients with chronic renal failure (CRF), develop multiple complications that are reminiscent of phenotypes observed in kl mutant mice. Furthermore, the kl gene is mainly expressed in kidney and brain. These evidences above suggest the possible involvement of Klotho function in the complications arising in CRF patients. To investigate the above possibility, we examined the kidneys of 10 clinically or histologically diagnosed CRF cases. The level of kl gene expression was measured by utilizing RNase protection assay. The expression of Klotho protein was assayed by utilizing Western blot analysis and by immunohistochemistry. The levels of kl mRNA expression were greatly reduced in all CRF kidneys. Moreover, the production of Klotho protein was also severely reduced in all CRF kidneys. These results suggest that the decrease in kl gene expression in CRF patients may underlie the deteriorating process of multiple complications in the CRF patients.

Adult↗
PubMed2001

Glycoprotein 130 regulates cardiac myocyte survival in doxorubicin-induced apoptosis through phosphatidylinositol 3-kinase/Akt phosphorylation and Bcl-xL/caspase-3 interaction.

BACKGROUND: We recently reported that the activation of glycoprotein (gp) 130 by leukemia inhibitory factor (LIF) upregulates Bcl-xL and exerts antiapoptotic effects in cardiac myocytes. In addition, LIF induces activation of phosphatidylinositol (PI) 3-kinase and Akt, which are known to be required for cell survival. However, their regulatory roles in cell death remain unknown. METHODS AND RESULTS: We investigated the fate of these proteins and the cytoprotective effects of LIF on doxorubicin (DOX)-induced apoptosis in cultured neonatal rat cardiac myocytes. Myocyte apoptosis increased significantly in DOX-treated cells but was significantly reduced by LIF pretreatment. The kinase activities of PI 3-kinase and Akt declined below basal levels but were partially recovered with LIF. Moreover, DOX-induced caspase-3 activation and decrease in Bcl-xL abundance are completely inhibited by LIF and caspase inhibitor. LIF phosphorylates Bad through PI 3-kinase and reduces the heterodimerization of Bad with Bcl-xL. Adenovirus transfer of the constitutively active form of Akt to cardiac myocytes restored cardiac myocyte survival after DOX treatment. Conversely, the dominant-negative form of Akt inhibited LIF-induced increase in cell viability and suppression of caspase-9 activation. CONCLUSIONS: Activation of gp130 inhibits DOX-induced cell death in cardiac myocytes, resulting in the restoration of PI 3-kinase/Akt activities and in the inactivation of caspase-3, leading to facilitation of the protective function of Bcl-xL.

Animals↗
PubMed2001

Signal transducer and activator of transcription (STAT)-induced STAT inhibitor 1 (SSI-1)/suppressor of cytokine signaling 1 (SOCS1) inhibits insulin signal transduction pathway through modulating insulin receptor substrate 1 (IRS-1) phosphorylation.

Signal transducer and activator of transcription (STAT)-induced STAT inhibitor 1 (SSI-1) is known to function as a negative feedback regulator of cytokine signaling, but it is unclear whether it is involved in other biological events. Here, we show that SSI-1 participates and plays an important role in the insulin signal transduction pathway. SSI-1-deficient mice showed a significantly low level of blood sugar. While the forced expression of SSI-1 reduced the phosphorylation level of insulin receptor substrate 1 (IRS-1), SSI-1 deficiency resulted in sustained phosphorylation of IRS-1 in response to insulin.Furthermore, SSI-1 achieves this inhibition both by binding directly to IRS-1 and by suppressing Janus kinases. These findings suggest that SSI-1 acts as a negative feedback factor also in the insulin signal transduction pathway through the suppression of IRS-1 phosphorylation.

Animals↗
PubMed2001

PKN delays mitotic timing by inhibition of Cdc25C: possible involvement of PKN in the regulation of cell division.

The role of PKN, a fatty acid- and Rho small GTPase-activated protein kinase, in cell-cycle regulation was analyzed. Microinjection of the active form of PKN into a Xenopus embryo caused cleavage arrest, whereas normal cell division proceeded in the control embryo microinjected with buffer or the inactive form of PKN. Exogenous addition of the active form of PKN delayed mitotic timing in Xenopus egg cycling extracts judging by morphology of sperm nuclei and Cdc2/cyclin B histone H1 kinase activity. The kinase-negative form of PKN did not affect the timing, suggesting that delayed mitotic timing depends on the kinase activity of PKN. The dephosphorylation of Tyr-15 of Cdc2 was also delayed in correlation with Cdc2/cyclin B histone H1 kinase activation in extracts containing active PKN. The Cdc25C activity for the dephosphorylation of Tyr-15 in Cdc2 was suppressed by pretreatment with the active form of PKN. Furthermore, PKN efficiently phosphorylated Cdc25C in vitro, indicating that PKN directly inhibits Cdc25C activity by phosphorylation. These results suggest that PKN plays a significant role in the control of mitotic timing by inhibition of Cdc25C.

Animals↗
PubMed2001

Interleukin-18 enhances the production of interleukin-8 by eosinophils.

Interleukin-18 (IL-18), a proinflammatory cytokine, leads to IFN-gamma production by NK or T cells, induces Th1 differentiation and suppresses IgE synthesis by B cells when acting on responding cells together with IL-12. IL-18 also exhibits biological activities related to allergic inflammation such as histamine or IL-4 release from basophils and accumulation of eosinophils in localized lesions in allergic model mice. In this study, Reverse transcription (RT)-PCR analysis revealed that IL-18 receptor alpha chain mRNA was expressed in both freshly prepared eosinophils and two eosinophilic cell lines (YY-1 and EoL-1 cells). Flow cytometry and RT-PCR analyses revealed that the treatment of YY-1 cells with n-butyric acid promoted cell maturation and caused an enhancement of IL-18 receptor alpha chain expression. IL-18 had little effect on the survival of peripheral eosinophils, but it dose-dependently augmented IL-8 synthesis by YY-1 cells. In addition, IL-18-mediated up-regulation of IL-8 expression in eosinophils from a patient suffering from hyper-eosinophilic syndrome was confirmed. Our findings using peripheral blood eosinophils and eosinophilic cell line suggest the functional importance of IL-18 in the induction of IL-8 and a potential proinflammatory role in allergy.

Butyric Acid↗
PubMed2001

Humanized antibody to human interleukin-6 receptor inhibits the development of collagen arthritis in cynomolgus monkeys.

In the present study, we demonstrated the anti-arthritic effect of humanized anti-human IL-6 receptor (IL-6R) antibody, MRA, in cynomolgus monkey. MRA can react with monkey IL-6R and block signal transduction of IL-6. Collagen-induced arthritis (CIA) was induced by twice immunizing with bovine type II collagen (CII) emulsified with complete adjuvant. MRA was intravenously injected once a week, from the day of the first collagen immunization, for 13 weeks. The symptoms of arthritis were evaluated using a visual scoring system and radiography. Inflammatory parameters (C-reactive protein (CRP), fibrinogen, and erythrocyte sedimentation rate (ESR) and concentrations of anti-CII antibody, anti-MRA antibody, and MRA were monitored regularly. At the end of the study, histological evaluation was carried out. MRA, at a dose of 10 mg/kg, gave rise to statistically significant suppression. The elevation of serum CRP and fibrinogen levels and ESR were also inhibited. Furthermore, radiographic and histological examination showed that MRA treatment suppressed joint destruction. Our results demonstrate that IL-6 plays an important role in monkey CIA and that MRA may be an attractive agent for the treatment of rheumatoid arthritis.

Animals↗
PubMed2001

Successful allogeneic stem cell transplantation from an unrelated donor for aggressive Epstein-Barr virus-associated clonal T-cell proliferation with hemophagocytosis.

We present here a case of aggressive Epstein-Barr virus (EBV)-associated clonal T-cell proliferation with hemophagocytosis that was successfully treated by allogeneic stem cell transplantation using an unrelated donor. A 17-year-old woman was admitted into the hospital with a high fever and liver dysfunction. Laboratory data including bone marrow aspiration revealed hemophagocytic syndrome with proliferation of immature T-lymphoid cells. The clonal proliferation of EBV-infected T cells was confirmed by Southern blot analysis using a terminal-repeat probe from the EBV genome and also by demonstrating T cell-receptor beta gene rearrangement. Intensive immunochemotherapy consisting of cyclosporin A, vincristine, etoposide, and high-dose methylprednisolone did not control the disease and relapse occurred repeatedly. Therefore, during remission after chemotherapy according to the CHOP-E regimen, the patient underwent allogeneic bone marrow transplantation (BMT) from an HLA-matched, unrelated donor. Donor selection was performed with help from the Japanese Association for Marrow Donor Program (JMDP). The patient has remained in good condition without recurrence of disease for 18 months after BMT. Allogeneic BMT is the treatment of choice for aggressive EBV-associated hemophagocytic lymphohistiocytosis even in the case where an HLA-matched sibling donor is not available, especially when the patient is refractory to intensive chemotherapy and/or there is a ready recurrence of disease after conventional therapy.

Adolescent↗
PubMed2001

Clinical features of polymyositis/dermatomyositis associated with silicosis and a review of the literature.

There are few reports which describe the association of polymyositis/dermatomyositis (PM/DM) and silicosis. The purpose of this study is to describe the clinical features of PM/DM associated with silicosis. We first describe clinical features of two cases and provide a review of the literature. Finally, seven patients with PM/DM associated with silicosis are retrospectively evaluated. There were one female and six males. Histological specimens were obtained by open lung biopsy in five cases and not examined in two. The mechanism of the association between silicosis and PM/DM is discussed.

Biopsy, Needle↗
PubMed2001

Isolation and characterization of a new immortal rat astrocyte with a high expression of NGF mRNA.

We have established a new line of immortalized rat astrocytes through transfection of plasmid pSV3-neo encoding the large T antigen of simian virus 40 into normal astrocytes. One of these immortalized astrocytes (ACT-57) with a flat and polygonal cell shape, exhibited stable growth in a chemically defined medium (modified N-2 medium) as well as in medium containing ordinary serum. ACT-57, retained a detectable level of expression of glial fibrillary acidic protein (GFAP) and its mRNA, and exhibited a stronger expression of nerve growth factor (NGF) mRNA than that of normal rat astrocytes or C6 glioma cells. NGF mRNA was significantly up-regulated by phorbol ester (12-O-tetradecanoylphorbol 13-acetate, TPA) and gamma-amino-n-butyric acid (GABA) but not by hydrocortisone. None of stimulants (TPA, dibutyryl cyclic AMP (db-cAMP), hydrocortisone, L-glutamate, carbacol, GABA, dopamine, or isoproterenol) changed the expression level of either brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT-3). There was a discrete difference between ACT-57 and normal astrocytes in the response to GABA and isoproterenol. These findings imply that normal cortical astrocytes possess a functional heterogeneity whereas the clonal astrocyte, ACT-57, does not, indicating that ACT-57 cells may be useful for in vitro studies of neuron-astrocyte interactions involving the induction of neurotrophic factors such as NGF.

Animals↗
PubMed2001

SOCS-1/SSI-1-deficient NKT cells participate in severe hepatitis through dysregulated cross-talk inhibition of IFN-gamma and IL-4 signaling in vivo.

Suppressor of cytokine signaling-1 (SOCS-1), also known as STAT-induced STAT inhibitor-1 (SSI-1), is a negative feedback molecule for cytokine signaling, and its in vivo deletion induces fulminant hepatitis. However, elimination of the STAT1 or STAT6 gene or deletion of NKT cells substantially prevented severe hepatitis in SOCS-1-deficient mice, while administration of IFN-gamma and IL-4 accelerated its development. SOCS-1 deficiency not only sustained IFN-gamma/IL-4 signaling but also eliminated the cross-inhibitory action of IFN-gamma on IL-4 signaling. These results suggest that SOCS-1 deficiency-induced persistent activation of STAT1 and STAT6, which would be inhibited by SOCS-1 under normal conditions, may induce abnormal activation of NKT cells, thus leading to lethal pathological changes in SOCS-1-deficient mice.

Animals↗
PubMed2001

The earliest stages of B cell development require a chemokine stromal cell-derived factor/pre-B cell growth-stimulating factor.

Environmental factors essential for the first stages of B lymphopoiesis remain elusive. Here, we report that immediately after commitment to B lineage, precursors become dependent on a chemokine SDF-1 and its receptor CXCR4 using mutant and radiation chimeric mice. In bone marrow, generation of the earliest identifiable B cell precursor populations requires CXCR4. In fetal liver, we identified Lin(-)CD19(-)c-kit(+)IL-7Ralpha(+)AA4.1(+), the earliest unipotent B cell precursor population, and found that its development was severely affected in SDF-1(-/-) embryos but not in IL-7(-/-) embryos. Lin(-) T cell progenitors appeared normal in SDF-1(-/-) embryos. Moreover, SDF-1 exhibited specific biologic activities on the earliest B cell precursors. SDF-1 provides the first example of a cytokine responsible for the earliest B lineage stages.

Animals↗
PubMed2001

Lipids of brush border membrane vesicles (BBMV) from Plutella xylostella resistant and susceptible to Cry1Ac delta-endotoxin of Bacillus thuringiensis.

Plutella xylostella (PX) that were 130000-fold more resistant to Cry1Ac were selected from the susceptible strain and maintained in the laboratory. The LC50 of the susceptible strain (PXS) was 0.38 microg toxin/g diet, whereas that of the resistant strain (PXR) was 4800 microg toxin/g diet. Brush border membrane vesicles (BBMV) were prepared from both PXS and PXR. In ligand blot analysis, Cry1Ac bound to a 120-kDa protein of BBMV; however, the intensity of the band was almost equal in both strains of insect. Hence, we analyzed the lipid components of BBMV from PXS and PXR. BBMV lipids were fractionated into non-polar lipid, phospholipid, neutral glycolipid and acidic glycolipid. Neutral glycolipid content was substantially lower in the BBMV of PXR than of PXS. The same trend was observed when lipids were extracted from whole midgut instead of BBMV. Thin layer chromatography of midgut neutral glycolipids revealed the presence of more than seven components. Among the midgut neutral glycolipids, a possible hexasaccharylceramide and a possible trisaccharylceramide of PXR were less than half the level found in PXS. The other lipid fractions in PXR and PXS were similar to each other.

Animals↗
PubMed2001

Spring balance evaluation of the ischiocavernosus muscle.

We studied the voluntary contractile activity of the ischiocavernosus muscle (ICM) in 21 sexually potent and 97 erectile dysfunction (ED) subjects using a spring balance. A strap was placed around the coronal grove of the glans penis and tensioned with the spring balance. Subjects were asked and encouraged to contract the ICM against the spring balance. We evaluated the length of stroke, duration of contraction, and maximum contractile force. The length of stroke, duration of contraction, and maximum contractile force showed statistically significant differences between potent and ED subjects. Diagnosed psychogenic ED and arteriogenic ED showed higher contractile activity than cavernous ED and neurogenic ED. Our results corresponded to those of previous studies that have urged consideration of the role of the ICM during the process of erection in animal experiments and in human electrophysiological studies. The spring balance evaluation is a useful, inexpensive method for evaluating the ICM.

Adolescent↗