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Biomedical subjects

F Shirakawa

Publications and source records attributed to F Shirakawa.

At least 19 recordsLinked to original sources
PubMed1996

Characterization and regulation of interleukin-4 receptor in adult T-cell leukemia cells.

We studied the expression of the receptor of interleukin (IL-4), one of the T cell growth factors, on fresh peripheral blood leukemic cells from adult T-cell leukemia (ATL) patients. Flow cytofluorometric analysis with a monoclonal antibody to the IL-4 receptor (IL-4R) were used to investigate whether expression of IL-4R on ATL cells is different from that on normal lymphocytes and other types of leukemic cells. Leukemic cells from acute type ATL patients synthesize IL-4R without stimulation, at levels much higher than normal resting lymphocytes and other types of leukemic cells. Furthermore, leukemic cells from acute type ATL showed higher IL-4R expression than that of chronic type ATL or human T-cell leukemia virus type I carriers. In addition, there was correlation between expression of IL-4R on the cell surface and the proliferative response to IL-4. Both IL-4 and IL-2 induced upregulation of IL-4R on activated normal T cells but not on ATL cells. These results suggest that abnormal expression of IL-4R may display different biological activities in ATL compared with other types of leukemia. Furthermore, the high expression of IL-4R in ATL may be involved in the proliferation of leukemic cells and the leukemogenesis in this disease.

Adult↗
PubMed1995

Interleukin-4 inhibits the production of interleukin-1 by adult T-cell leukemia cells.

Freshly isolated leukemic cells from patients with adult T-cell leukemia (ATL) produce high levels of interleukin-1 (IL-1), which is believed to play an important role in neutrophilia, elevation of C-reactive protein, osteolytic bone lesions, hypercalcemia, and fever in ATL. However, relatively little is known regarding the regulatory mechanism of IL-1 production in ATL. Interleukin-4 (IL-4) affects the monocytes- and neoplastic cells-mediated cytokine production. In this study, we investigated the effect of IL-4 on IL-1 alpha and IL-1 beta production by ATL cells in vitro. IL-4 was found to markedly inhibit the release of IL-1 alpha and IL-1 beta into the conditioned medium in a dose-dependent manner. Northern blot analysis of steady-state IL-1 mRNA demonstrated that IL-4 treatment of ATL cells resulted in a reduction of IL-1 mRNA. These results support the notion that ATL cells spontaneously produce IL-1 alpha and IL-1 beta; however, such production can be inhibited by the immunomodulating agent, IL-4. IL-4 may play an important regulatory role in the production of IL-1 in ATL.

Aged↗
PubMed1995

Siblings with ACTH insensitivity due to lack of ACTH binding to the receptor.

We report two siblings, a 9-year-old boy and 4-year-old girl, with ACTH insensitivity. They were referred to our hospital because of pigmentation of the skin. They had normal plasma cortisol and urinary 17-OHCS levels despite markedly high plasma ACTH, and these did not respond to consecutive 3-day ACTH-Z administration, but plasma aldosterone responded normally to increased plasma renin activity after a low sodium diet. We examined the characteristics of ACTH receptors in peripheral blood mononuclear leukocytes (MNLs) obtained from the patients and their family. Adenylate cyclase generation caused by an addition of ACTH did not occur in MNLs from the patients. In studies on ACTH binding to MNLs, a lack of high-affinity ACTH binding was observed in the patients. These results suggest that the patients have a defect in ACTH binding to the receptors, resulting in ACTH insensitivity. The reason for this defect in ACTH binding remains unclear because no significant mutation in the ACTH receptor DNA sequence was detected in the MNLs of these patients.

17-Hydroxycorticosteroids↗
PubMed1995

Human T-cell leukemia virus type I tax transactivates the interleukin-6 gene in human rheumatoid synovial cells.

OBJECTIVE: To determine the effect of the human T cell leukemia virus type I (HTLV-I) tax gene on interleukin-6 (IL-6) production and gene transcription in synovial cells, we established the synovial cell line, E-11, from a patient with rheumatoid arthritis. METHODS: E-11 cells were transfected with tax expression vector using the calcium phosphate coprecipitation method. IL-6 production and gene expression were investigated by ELISA and Northern blot analysis, respectively. To clarify how tax induces IL-6 gene expression, we used deletion analysis and chloramphenicol acetyltransferase (CAT) assay, and electrophoretic mobility shift assay (EMSA). RESULTS: Transfection of the tax gene induced markedly high levels of IL-6 mRNA. Furthermore, the tax gene strongly transactivated IL-6 gene promoter activity assayed by CAT assay. By using deletion and site specific mutations, we have identified a nuclear factor (NF)-kappa B sequence (positions -73 to -63) which is essential for tax transaction. EMSA demonstrated the induction of specific binding of nuclear extracts to the NF-kappa B sequence by HTLV-I tax. CONCLUSION: The HTLV-1 tax gene may transactivate IL-6 gene in the synovial cells through NF-kappa B and may contribute in the pathophysiology of HTLV-I associated arthritis.

Arthritis, Rheumatoid↗
PubMed1994

Transcriptional regulation of the human interleukin-6 gene promoter in human T-cell leukemia virus type I-infected T-cell lines: evidence for the involvement of NF-kappa B.

Freshly isolated leukemic cells from patients with adult T-cell leukemia (ATL) and human T-cell leukemia virus type I (HTLV-I)-infected T-cell lines constitutively produce high levels of interleukin-6 (IL-6) protein and mRNA. To clarify the mechanisms that lead to the activation of IL-6 gene in HTLV-I-infected cells, we first studied the regulatory regions in the IL-6 gene transcription by transfection of chloramphenicol acetyltransferase (CAT) reporter plasmids containing the IL-6 promoter. When transfected into HTLV-I-infected T-cell lines MT-2 and HUT-102, IL-6 promoter/CAT plasmids were strongly activated without any stimulation. By deletion analysis of 5' upstream region of IL-6 promoter, the DNA region between -73 and -59 bp from the transcription start site of IL-6 gene was important in the expression of IL-6/CAT activities in HTLV-I-infected cells. This region contains nuclear factor (NF)-kappa B binding site. The site-directed mutation of the kappa B motif in IL-6/CAT plasmid resulted in the complete abrogation of IL-6 promoter activity in these cells. Furthermore, when IL-6 promoter/CAT plasmid was introduced into an HTLV-I-uninfected T-cell line, Jurkat, IL-6 promoter activity was silent in the basal level, but strongly increased by the cotransfection with an HTLV-I tax expression plasmid. However, tax expression plasmid showed no transactivation activity, when kappa B site was mutated in IL-6 promoter/CAT plasmid. We found that the IL-6 kappa B site specifically formed a complex with NF-kappa B-containing nuclear extracts from MT-2 and HUT-102 cells. Finally, transfection of HTLV-I tax into Jurkat cells resulted in induction of specific binding of nuclear extracts to the NF-kappa B sequence. These results strongly suggest that HTLV-I tax gene may transactivate IL-6 gene through kappa B site in HTLV-I-positive T-cell lines and activation of NF-kappa B may be crucial in HTLV-I-induced IL-6 gene activation in ATL.

Base Sequence↗
PubMed1994

Stimulatory effect of IL-1 beta on catecholamine secretion from cultured bovine adrenal medullary cells.

We investigated the effect of recombinant human interleukin-1 beta (IL-1 beta) on catecholamine secretion from cultured bovine adrenal medullary cells. Treatment of cultured cells with IL-1 beta (10 ng/ml) for 24 hr caused an increase in accumulation of catecholamines in the cultured medium. The accumulation of catecholamines stimulated by IL-1 beta was observed in time (4-48 hr)- and concentration (3-30 ng/ml)-dependent manners. The stimulatory effect of IL-1 beta (10 ng/ml) was completely inhibited by recombinant human IL-1 receptor antagonist (1 microgram/ml). IL-1 beta had little effect on [3H]norepinephrine uptake to cultured cells. These results suggest that IL-1 beta stimulates catecholamine secretion through activation of IL-1 receptors in adrenal medullary cells.

Adrenal Medulla↗
PubMed1994

Interleukin-1 alpha as an autocrine growth factor for acute lymphoblastic leukaemia cells.

We describe a case of B-lineage acute lymphoblastic leukaemia (ALL) with proliferation of leukaemic cells through an interleukin-1 alpha (IL-1 alpha) autocrine mechanism. Flow cytometric analysis using the IL-1 receptor type II (IL-1Rt II) monoclonal antibody (mAb) demonstrated the expression of the IL-1Rt II on leukaemic cells: this is the first report in IL-1RtII-positive freshly isolated ALL cells from a patient. In accordance with the expression of IL-1RtII, the leukaemic cells proliferated in response to exogenous IL-1 alpha. In addition, anti-IL-1 alpha mAb markedly inhibited the spontaneous cell proliferation. Furthermore, Northern blot analysis detected IL-1 alpha mRNA without any stimulation. These observations suggest that IL-1 alpha may play an important role as an autocrine growth factor in some cases of ALL.

Adult↗
PubMed1993

Inhibitory effect of interleukin 4 on production of interleukin 6 by adult T-cell leukemia cells.

Freshly isolated leukemic cells from patients with adult T-cell leukemia (ATL) produce high levels of interleukin 6 (IL-6), which is suggested to play an important role in thrombocytosis, elevation of C-reactive protein, and hypercalcemia in ATL. In this study, we investigated the effects of T-cell growth factors such as interleukin 2 (IL-2) and interleukin 4 (IL-4) on IL-6 production by ATL cells in vitro. Although IL-2 and/or IL-4 enhanced the cell proliferation of freshly isolated ATL cells from seven of nine patients, IL-2 did not affect the IL-6 release in most cases. In contrast, another T-cell tropic factor, IL-4 markedly inhibited the release of IL-6 in the conditioned medium in all cases. This IL-4-mediated inhibition of IL-6 release was completely abrogated by the addition of anti-IL-4 monoclonal antibody. Time course experiments demonstrated that IL-4 reduced the secretion of IL-6 for a prolonged period of time (more than 72 h). By Northern analysis, IL-4 reduced the transcription level of IL-6 mRNA. Furthermore, by flow cytofluorometry with the use of anti-human IL-4 receptor monoclonal antibody, ATL cells showed the significant level of IL-4 receptor on their cell surfaces without any stimulation. These data suggest that IL-4 may play an important regulatory role in the production of IL-6 in ATL.

Aged↗
PubMed1993

Suppressive effect of interleukin-4 on the differentiation of M1 and HL60 myeloid leukemic cells.

The effect of interleukin-4 (IL-4) on the proliferation and differentiation of myeloid leukemic cell lines was studied in vitro. A culture of murine myeloid cell line, M1, with lipopolysaccharide (LPS) from Escherichia coli, induced differentiation into macrophages that expressed Fc receptors and phagocytic activity. IL-4 did not induce the differentiation of M1 cells but inhibited the differentiation of M1 cells induced with LPS. On the other hand, LPS arrested the proliferation of M1 cells. IL-4 had no effect on the proliferation of M1 cells but restored the LPS-induced arrest of the proliferation of M1 cells. IL-1, IL-6 and tumor necrosis factor alpha (TNF-alpha) also induced the differentiation of M1 cells into macrophages and arrested proliferation. IL-4 suppressed the IL-1-, IL-6-, and TNF-induced differentiation of M1 cells and restored the arrested proliferation with IL-1, IL-6, and TNF. Similar results were obtained with human myeloid cell line HL60. These results suggest that IL-4 has a suppressive effect on the differentiation of myeloid cells into macrophages.

Animals↗
PubMed1993

Enhancing effect of interleukin-2 on production of parathyroid hormone-related protein by adult T-cell leukemia cells.

Leukemic cells from patients with adult T-cell leukemia (ATL) can produce a calcium-regulating protein, parathyroid hormone-related protein (PTHrP). Moreover, it has been reported that ATL cells produce some cytokines besides PTHrP and that these cells respond to the T-cell growth factors, interleukin-2 (IL-2) and interleukin-4 (IL-4). To elucidate whether PTHrP produced by ATL cells is regulated by IL-2 or IL-4, we investigated the in vitro effects of IL-2 and IL-4 on the release of PTHrP. IL-2 increased the release of PTHrP into the conditioned medium from leukemic cells in some, but not all, ATL patients; however, IL-4 did not affect the PTHrP release. PTHrP messenger RNA (mRNA) levels were increased in ATL cells cultured in the presence of IL-2. These data suggest that IL-2 plays a role in the regulation of hypercalcemia by enhancing the production of PTHrP in ATL patients.

Aged↗
PubMed1993

The human prointerleukin 1 beta gene requires DNA sequences both proximal and distal to the transcription start site for tissue-specific induction.

In these studies, we have identified DNA sequences and specific protein interactions necessary for transcriptional regulation of the human prointerleukin 1 beta (proIL-1 beta) gene. A cell-type-independent lipopolysaccharide (LPS)-responsive enhancer element located between -3757 and -2729 bp upstream from the transcription start site (cap site) consisted of at least six discrete subregions which were essential to the maximal induction by LPS in transfected monocytes. The enhancer also appeared to mediate phorbol myristate acetate induction in monocytes and IL-1 responsiveness in fibroblasts. Deletion and base substitution mutations along with DNA binding studies demonstrated that the enhancer contained a minimum of three functional protein binding sequences, two of which appeared to be important for gene induction. One of the essential proteins which bound to the enhancer was similar or identical to members of the C/EBP family of transcription factors required for both IL-1- and LPS-specific induction of the IL-6 gene (i.e., the NF-IL6 proteins). When ligated to the proIL-1 beta cap site-proximal region (located between -131 to +12), both the proIL-1 beta and the simian virus 40 enhancer elements functioned more efficiently in monocytes than in HeLa cells, which are not normally competent for IL-1 beta expression. When ligated to the murine c-fos promoter, however, the proIL-1 beta enhancer was inducible in phorbol myristate acetate-stimulated HeLa cells, suggesting the existence of a proIL-1 beta promoter-proximal requirement for tissue specificity.

Animals↗
PubMed1989

Signal transduction pathway for IL-1. Involvement of a pertussis toxin-sensitive GTP-binding protein in the activation of adenylate cyclase.

Human Il-1 alpha induces the synthesis of kappa Ig L chains by the pre-B cell line 7OZ/3, IL-2R alpha by the human NK cell line YT, and PGE2 by human rheumatoid synovial cells. Pertussis toxin (PT) markedly inhibited all three IL-1-induced activation events. The inhibition by PT was associated with a decrease in IL-1-mediated cAMP production. PT also inhibited IL-1-stimulated cAMP production in crude membrane fractions from 7OZ/3, YT, and 3T3 fibroblasts. In addition, IL-1 stimulated GTPase activity present in the membranes IL-1-responsive cells. Furthermore, the IL-1-induced GTPase activity was sensitive to PT. PT induced the ADP-ribosylation of a 46-kDa substrate in membrane preparations from IL-1-responsive cells. Cholera toxin also induced the ADP-ribosylation of a 46-kDa substrate in the same membrane preparations. The present findings indicate that the IL-1R is linked to a PT-sensitive G protein that stimulates the activity of adenylate cyclase.

Adenosine Diphosphate Ribose↗
PubMed1989

Autocrine stimulation of interleukin 1 alpha in the growth of adult human T-cell leukemia cells.

In a previous study, we reported that adult T-cell leukemia (ATL) cells produce interleukin 1 (IL1)-like factors that stimulate murine thymocyte proliferation, the production of interleukin 2 (IL2), and the expression of IL2 receptors (IL2R) on normal human T-cells in the presence of concanavalin A. In this communication, we studied the effect of IL1 on the growth of ATL cells in vitro. When ATL cells freshly obtained from patients were cultured with recombinant (r) human IL1 alpha, IL1 beta, or IL1-like factors produced by ATL cell lines, the growth of ATL cells was stimulated in a concentration-dependent manner. Maximum stimulation was observed at a concentration of 50-100 units/ml of IL1. The expression of IL2R on ATL cells was also enhanced by IL1, but the production of IL2 was not induced. These effects of rIL1 alpha or beta were specifically inhibited by anti-IL1 alpha or anti-IL1 beta antibody. Furthermore, the spontaneous growth of ATL cells was also inhibited by anti-IL1 alpha antibody, but not by anti-IL1 beta antibody. ATL cells exhibited enhanced expression of IL1 receptors on their surface as detected by the binding of 125I-labeled rIL1 alpha. These results suggest that IL1 alpha produced by ATL cells stimulates the growth of ATL cells by an autocrine mechanism.

Humans↗
PubMed1989

Expression of IL-1 receptors on human peripheral B cells.

The expression of IL-1R on human peripheral B cells was analyzed by the binding assay with 125I-labeled human rIL-1 alpha and by the flow cytofluorometry by the use of FITC-conjugated IL-1 alpha. The proliferation and the differentiation of B cells stimulated with Staphylococcus aureus Cowan I (SAC) in the presence of T cell-derived factors were dependent on IL-1. By the binding experiment with 125I-labeled IL-1 alpha, B cells expressed only few IL-1R without any stimulations. When they were stimulated with SAC, IL-1R on B cells began to increase by only 1 h, reached the maximum level at 6 h. The binding of 125I-labeled IL-1 alpha to B cells was inhibited by the addition of either cold IL-1 alpha or IL-1 beta suggesting that IL-1R on B cells reactive for IL-1 alpha and IL-1 beta were identical. By Scatchard plot analysis, the existence of two classes of IL-1R on B cells was found. A major class of IL-1R (320 molecules/cell) has a lower affinity (Kd = 3.8 x 10(-10) M) and a minor class of IL-1R (70 molecules/cell) has a higher affinity (Kd = 4.4 x 10(-12) M). When B cells were stimulated with SAC, both lower and higher affinity IL-1R were increased to 1960 molecules/cell and 300 molecules/cell, respectively. Furthermore, IL-1R on B cells were also detected with FITC-conjugated IL-1 alpha by a flow cytofluorometer. Only 3 to 5% of B cells expressed IL-1R without any stimulations. When B cells were stimulated with SAC, IL-1R-positive B cells were increased to 20%. The addition of anti-class II antibodies inhibited B cell proliferation and differentiation induced with SAC, IL-1, and T cell-derived factors. Anti-class II antibodies also inhibited the number of IL-1R on B cells. These results suggest that the expression of IL-1R was induced as the initial stage of B cell activation and that class II Ag play an important role for the expression of IL-1R on B cells.

Antibodies, Monoclonal↗
PubMed1989

Circulating monocyte (macrophage)-specific antibodies in patients with autoimmune thyroid diseases.

We investigated the presence of circulating monocyte-specific antibodies (monocytotoxic activities) by a complement-dependent cytotoxicity test and the relations between these monocytotoxic activities and other immunological indices in patients with autoimmune thyroid diseases. Antibodies reactive for monocytes (macrophages) were found in the sera from patients with autoimmune thyroid diseases. These antibodies were present in both IgG and IgM fractions and specific for monocytes since they were absorbed by monocytes but not by lymphocytes or granulocytes; furthermore, lymphocytotoxic and granulocytotoxic activities were not changed after the absorption of the sample sera by monocytes. Also, these antibodies did not have cross-reactivity to thyroid-specific antigens demonstrated by absorption tests and their specificity was different from anti HLA-DR antibody demonstrated by a flow cytofluorometric analysis. Monocyte-specific antibodies are reactive for autologous monocytes as well as allogenic monocytes. Patients who had positive monocytotoxic activities had high levels of TSH receptor antibodies (TRAb) and antimicrosomal antibodies in Graves' disease, and monocytotoxic activities were significantly correlated with the levels of TRAb in Graves' disease. These results suggest that the monocyte-specific antibodies (monocytotoxic activities) were significantly correlated with the immunological activities in Graves' disease.

Adolescent↗
PubMed1989

Interleukin 1 and cyclic AMP induce kappa immunoglobulin light-chain expression via activation of an NF-kappa B-like DNA-binding protein.

Interleukin 1 (IL-1) induces the synthesis of kappa immunoglobulin light chains and the expression of surface immunoglobulin in the murine pre-B-cell line 70Z/3 (J. G. Giri, P. W. Kincade, and S. B. Mizel, J. Immunol. 132:223-228, 1984). In the present study, we found that these effects of IL-1 are mimicked by cyclic AMP (cAMP) analogs and cAMP-elevating drugs. The induction of kappa immunoglobulin light-chain gene expression by IL-1 was associated with an increase in intracellular cAMP levels. Incubation of 70Z/3 cells with IL-1 or cAMP resulted in the activation of the kappa immunoglobulin enhancer, as detected by the induction of chloramphenicol acetyltransferase (CAT) in cells transfected with a kappa enhancer-CAT expression plasmid. In contrast, CAT plasmids lacking a kappa immunoglobulin enhancer were inactive in the presence of IL-1 or cAMP. Furthermore, IL-1 and cAMP analogs and inducers were found to induce the activation of a NF-kappa B-like DNA-binding protein that exhibited specificity for the kappa immunoglobulin enhancer. These results suggest that cAMP may play an important role as a second messenger for IL-1 in the induction of kappa immunoglobulin light-chain synthesis in pre-B cells via the activation of a DNA-binding protein that is similar or identical to NF-kappa B.

Animals↗