[Behçet's disease].
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Anti-Inflammatory Agents↗
Biomedical subjects
T Sakane
Publications and source records attributed to T Sakane.
Behçet's disease.
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Anti-Inflammatory Agents↗
Txk, a nonreceptor tyrosine kinase of the Tec family, is expressed in T helper type 1 cells and regulates interferon gamma production in human T lymphocytes.
Differentiation of human T cells into T helper (Th)1 and Th2 cells is vital for the development of cell-mediated and humoral immunity, respectively. However, the precise mechanism responsible for the Th1 cell differentiation is not fully clarified. We have studied the expression and function of Txk, a member of the Tec family of nonreceptor tyrosine kinases. We found that Txk expression is restricted to Th1/Th0 cells with IFN-gamma producing potential. Txk transfection of Jurkat T cells resulted in a several-fold increase of IFN-gamma mRNA expression and protein production; interleukin (IL)-2 and IL-4 production were unaffected. Antisense oligodeoxynucleotide of Txk specifically inhibited IFN-gamma production of normal peripheral blood lymphocytes, antigen-specific Th1 clones, and Th0 clones; IL-2 and IL-4 production by the T cells was unaffected. Txk cotransfection led to the enhanced luciferase activity of plasmid (p)IFN-gamma promoter/enhancer (pIFN-gamma[-538])-luciferase-transfected Jurkat cells upon mitogen activation. Txk transfection did not affect IL-2 and IL-4 promoter activities. Thus, Txk specifically upregulates IFN-gamma gene transcription. In fact, Txk translocated from cytoplasm into nuclei upon activation and transfection with a mutant Txk expression plasmid that lacked a nuclear localization signal sequence did not enhance IFN-gamma production by the cells, indicating that nuclear localization of Txk is obligatory for the enhanced IFN-gamma production. In addition, IL-12 treatment of peripheral blood CD4(+) T cells enhanced the Txk expression, whereas IL-4 treatment completely inhibited it. These results indicate that Txk expression is intimately associated with development of Th1/Th0 cells and is significantly involved in the IFN-gamma production by the cells through Th1 cell-specific positive transcriptional regulation of the IFN-gamma gene.
Cell Differentiation↗
Effects of cigarette smoking on Fas/Fas ligand expression of human lymphocytes.
Cigarette smoking has been shown to affect human immune responses. We have studied Fas/Fas ligand (FasL) expression, which is involved in the cytotoxic activity, immune privilege, and self-tolerance, and other apoptosis-associated molecule expression of peripheral blood lymphocytes (PBL) in healthy subjects with/without cigarette smoking. We found that expression of FasL protein was detected marginally in the fresh PBL and was induced upon mitogen activation in normal individuals without smoking. In contrast, fresh PBL from those with chronic cigarette smoking exhibited enhanced expression of FasL protein without in vitro mitogen stimulation. Moreover, mitogen stimulation failed to augment FasL protein expression of their lymphocytes, suggesting dysregulation of FasL expression of PBL in individuals with cigarette smoking. In contrast, Fas, Bcl-2, and p53 expression were not significantly different between normal individuals with chronic cigarette smoking and those without smoking. In addition, we found that in vitro brief treatment with nicotine induces and/or enhances FasL mRNA and protein expression of lymphocytes from normal donors without smoking. These results suggest that aberrant FasL expression of lymphocytes is, at least in part, involved in the immune impairment in individuals with chronic cigarette smoking.
Adult↗
A study of novel antiallergic agents with eosinophilic infiltration inhibiting action.
The antiallergic action of a series of novel mono-O-substituted trimethylhydroquinones was investigated. Among this series of the compounds, 4-[4-[4-(diphenylmethyl)-1-piperazinyl]butoxy]-2,3,6- trimethylphenol (compound 3) showed a potent antihistaminic action (pA2 = 7.11) and an antiasthmatic action (100 mg/kg. p.o) on sensitized guinea pigs. Moreover, this compound exhibited a strong eosinophilic infiltration inhibiting action on sensitized mice (100 mg/kg p.o.).
Albumins↗
Evidence for neural regulation of inflammatory synovial cell functions by secreting calcitonin gene-related peptide and vasoactive intestinal peptide in patients with rheumatoid arthritis.
OBJECTIVE: To elucidate the possible involvement of the nervous system in the regulation of pathophysiologic responses in patients with rheumatoid arthritis (RA), we examined the expression of peripheral nerves containing the neuropeptides calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) in RA synovium and their effects on RA synovial cell functions. METHODS: The effects of CGRP and VIP on proinflammatory cytokine and matrix metalloproteinase (MMP) production by RA synovial cells were estimated by enzyme-linked immunosorbent assay, and their messenger RNA (mRNA) expression by reverse transcription-polymerase chain reaction (RT-PCR) using limiting dilutions of the complementary DNA. Expression of CGRP receptors (CGRPRs) and VIP receptors (VIPRs) on RA synovial cells was assessed by RT-PCR and radioreceptor assays. The functions of CGRPRs and VIPRs of the synovial cells were studied by using a CGRPR antagonist and a VIPR antagonist, respectively. RESULTS: CGRP and VIP inhibited the proliferation of, and the proinflammatory cytokine and MMP production by, RA synovial cells at the level of mRNA expression. Expression of CGRPR and VIPR on RA fibroblast-like synovial cells was confirmed by RT-PCR and radioreceptor assays. Functions of the neuropeptide receptors were inhibited by their receptor antagonists. CGRP and VIP inhibited nuclear translocation and phosphorylation of the transcription factor cAMP response element binding protein in RA synovial cells. CONCLUSION: CGRP and VIP inhibited excessive synovial cell functions, which suggests neural regulation of inflammatory responses in patients with RA and possible clinical application of the neuropeptides.
Adult↗
The female X-inactivation mosaic in SLE.
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Antigen-Presenting Cells↗
Purification and gene cloning of a chitosanase from Bacillus ehimensis EAG1.
Bacillus ehimensis EAG1 (IFO15659) produced and secreted chitosanase in the presence of exogenous chitosan. The chitosanase was purified from the culture filtrate of the bacterium to apparent homogeneity in SDS-polyacrylamide gel electrophoresis. The purified enzyme had a molecular weight of approximately 31,000. A 1.9-kbp DNA fragment containing the chitosanase gene was cloned and the complete nucleotide sequence was determined. The sequence was found to contain a single open reading frame encoding a protein of 302 amino acids. The deduced amino acid sequence showed significant homology with the chitosanase from Bacillus circulans MH-K1.
Journal Article↗
Corynebacterium terpenotabidum sp. nov., a bacterium capable of degrading squalene.
The taxonomic status of Arthrobacter sp. Y-11T, which was described as a squalene-degrading bacterium, was investigated by chemotaxonomic and genetic methods. The strain possesses wall chemotype IV, MK-9(H2) as the predominant menaquinone, mycolic acids, and straight-chain, saturated and monounsaturated fatty acids, with considerable amounts of tuberculostearic acid. The DNA G+C content is 67.5 mol%. 16S rRNA gene sequence analysis and quantitative DNA-DNA hybridization experiments provided strong evidence that strain Y-11T represents a new species within the genus Corynebacterium, for which the name Corynebacterium terpenotabidum sp. nov. is proposed. The type strain of C. terpenotabidum is strain Y-11T (= IFO 14764T).
Base Sequence↗
Protein tyrosine phosphorylation: A possible common signaling pathway in human Th1 and Th2 cell clones.
BACKGROUND: It has been reported that protein tyrosine phosphorylation is essential for cytokine production in mouse Th1 cells but not in Th2 cells. However, little is known about the difference of signal transduction between human antigen-specific Th1 and Th2 cell clones. METHODS: Purified protein derivative-specific Th1 and Dermatophagoides farinae-specific Th2 cell clones were established. T cell clones were stimulated with anti-CD3 Abs and further treated with goat antimouse immunoglobulin Abs for cross-linking of TCR/CD3 complex. RESULTS: In contrast to murine Th2 clones, tyrosine phosphorylation including both ZAP-70 and phospholipase-C-Al was necessary for cell activation in both types of human T cell clones. This was further supported by the observation that genistein (protein tyrosine kinase inhibitor) inhibits IFN-A production for Th1 and IL-4 for Th2 in a dose-dependent manner. CONCLUSION: Protein tyrosine phosphorylation is thus an essential component in transducing the activation signal from TCR-CD3 complex both in human Th1 and Th2 cells.
Clone Cells↗
Effects of thyroid hormones on apoptotic cell death of human lymphocytes.
Apoptosis plays a critical role in the development and homeostasis of tissues, especially those with high cell turnover such as the lymphoid system. We have examined the effects of thyroid hormones, TSH and TRH, on apoptosis of human T lymphocytes. We found that T lymphocytes cultured with T3 and T4, but not TSH nor TRH, in vitro showed enhanced apoptosis, evidenced by DNA ladder formation and characteristic morphological changes. In addition, prolonged cultivation with thyroid hormones of the lymphocytes further enhanced the extent of apoptosis. We also found that treatment with thyroid hormones of T lymphocytes induced reduction of mitochondrial transmembrane potential (delta psi) and production of reactive oxygen species, both of which are intimately associated with apoptotic cell death. In addition, cellular expression of antiapoptotic Bcl-2 protein was clearly reduced by the treatment of lymphocytes with thyroid hormones in vitro. Thus, T lymphocytes treated with thyroid hormones accompany reduction of Bcl-2 protein expression, production of reactive oxygen species, and reduction of mitochondrial delta psi, resulting in apoptotic lymphocyte death. Moreover, we found that lymphocytes in patients with Graves' disease showed enhanced apoptosis compared with those in normal individuals. These results suggest that thyroid hormones have the potential to induce apoptotic cell death of human lymphocytes in vivo and in vitro.
Adult↗
Transnasal delivery of 5-fluorouracil to the brain in the rat.
The purpose of this research is to clarify the feasibility and to determine the extent of transnasal drug delivery to the brain through the cerebrospinal fluid (CSF) in the rat, using 3H-5-fluorouracil (5FU) as a model drug. It was confirmed first that the concentration of 5FU in the CSF was significantly higher following nasal administration compared with intravenous injection, indicating direct transport of 5FU from the nasal cavity to the CSF. Concentration-time profiles of 5FU in the plasma and in the cerebral cortex were determined following intravenous infusion, nasal instillation and nasal perfusion. In order to evaluate the extent of drug transport from the nasal cavity to the cerebral cortex by way of the CSF, the apparent brain uptake clearances were calculated. The uptake clearance following nasal perfusion (8.65 microl/min/g tissue) was significantly large (p < 0.001) in comparison with that following intravenous infusion (6.20 microl/min/g tissue), while that following nasal instillation (6.94 microl/min/g tissue) was not. Consequently, significant amount of 5FU is transported from the nasal cavity to the brain through the CSF and thus, the delivery of the hydrophilic drug to the brain is augmented by nasal drug application.
Administration, Intranasal↗
[Endothelial-derived nitric oxide mediates the peripheral vasodilatory effects of amrinone in humans].
Amrinone, which is used for the treatment of acute congestive heart failure, has vasodilatory and positive inotropic effects through the increment of intracellular cyclic adenosine monophosphate. Recent in vitro investigations have shown that amrinone has an endothelium-dependent vasodilatory effect. The present study examined whether amrinone shows this endothelium-dependent vasodilatory effect in human peripheral vessels. Forearm blood flow during intra-arterial infusion of graded doses (12.5, 25, 50, 100, 200 micrograms/min) of amrinone was measured using plethysmography in 10 healthy subjects without organic vascular disease before and after nitric oxide synthase blocking with NG-monomethyl-L-arginine (L-NMMA, 400 mumol). The graded dose of amrinone produced progressive increases in amrinone plasma concentrations, and a dose over 100 micrograms/min caused amrinone plasma concentrations of more than 1.0 microgram/ml. The increase in forearm blood flow in response to amrinone was significantly depressed after L-NMMA doses of less than 100 micrograms/min, but the increase in forearm blood flow during infusion of higher doses (100, 200 micrograms/min) was not affected by L-NMMA. These results suggest that endothelial-derived nitric oxide may partially contribute to amrinone-induced vasodilation in humans. Thus, the vasodilatory effect of amrinone might be impaired in patients with endothelial dysfunction.
Adult↗
[The most recent advance in clinical investigation of rheumatoid arthritis].
The pathogenesis of rheumatoid arthritis (RA) can be explained through two main hypotheses: T cell-dependent and T cell-independent pathways. The mesenchymal hypothesis has proposed that after an initiation event triggered by T cells, synovitis is maintained by a proinflammatory cytokine cascade, chiefly a TNF-alpha dependent cytokine cascade involving macrophages and synovial fibroblasts. T cells rather may not be important in perpetuating disease at the chronic stages. The T cell hypothesis has proposed that T cells are continuously involved in the pathogenesis of RA from its initiation phase through to the chronic stages. At the latter stages, T cells are importantly concerned in the cytokine network in rheumatoid joints. This paper reviews recent work in this area, and suggests that synergistic approaches targeting the two key aspect of the pathogenesis, T cells and the TNF-dependent cytokine cascade may be the best approach toward attempting a cure of RA.
Animals↗
Prolactin locally produced by synovium infiltrating T lymphocytes induces excessive synovial cell functions in patients with rheumatoid arthritis.
OBJECTIVE: To elucidate the role of prolactin (PRL) produced in joints as part of the pathological response of rheumatoid arthritis (RA), we studied PRL production and prolactin receptor (PRLR) expression in RA synovium and its effects on RA synovial cell functions. METHODS: Proinflammatory cytokine and matrix metalloproteinase (MMP) production by RA synovial cells was estimated by ELISA, Western blotting analysis, and zymography. Expression of PRLR by RA synovial cells and local production of PRL were estimated by reverse transcription polymerase chain reaction and immunohistochemical staining. RESULTS: PRL enhanced RA synovial cell proliferation. Production of proinflammatory cytokine and MMP was augmented and production of tissue inhibitor of metalloproteinases (TIMP)-1 was inhibited by PRL treatment of RA synovial cells, suggesting that PRL enhances total collagenase activity in the joints. PRLR was exclusively expressed on fibroblast-like synovial cells and lymphocytes infiltrating into the synovium in patients with RA. Both synovium infiltrating T lymphocytes and, to a lesser extent, fibroblast-like synovial cells synthesized PRL, suggesting that PRL acts as a paracrine as well as autocrine activator of RA synovial cell functions. Stimulation of synovial cells by PRL induced rapid translocation of STAT-5 from cytoplasm into nuclei of RA synovial cells, suggesting that transcriptional regulation of RA synovial cell functions by PRL affects STAT-5. Inhibitors of PRL release, such as bromocriptine, inhibited proliferation of proinflammatory cytokines and collagenases by RA synovial cells. CONCLUSION: Our findings emphasize the importance of PRL, locally produced by infiltrating T lymphocytes, for aberrant synovial cell functions in RA, and suggest possible clinical application of PRL inhibitors.
Aged↗
Synovium infiltrating T cells induce excessive synovial cell function through CD28/B7 pathway in patients with rheumatoid arthritis.
OBJECTIVE: To clarify involvement of synovial T cells in the development of synovial inflammation in patients with rheumatoid arthritis (RA), we analyzed cellular interactions between synovial cells and infiltrating T cells via CD28/B7-1 and B7-2. METHODS: Synovial cells and infiltrating T cells were recovered separately from RA synovial tissues. Expression of CD28, B7-1, and B7-2 of synovial cells was analyzed by immunohistochemical staining and immunofluorescence analysis. Interleukin 1beta (IL-1beta), IL-6, and matrix metalloprotease 3 (MMP-3) secreted by synovial cells in the presence of infiltrating T cells were measured by ELISA. Nuclear transcription factor CD28 responsive complex was detected by a gel shift assay. RESULTS: Both CD28+ T cells and B7-1/B7-2+ cells were found accumulating in the mononuclear cell infiltrate of RA synovial tissues and B7-1/B7-2+ cells were mainly LeuM3+ synovial cells. CD28 responsive complex was detected in nuclear extracts of freshly isolated lymphocytes from RA synovial tissues, but not those from osteoarthritis synovial tissues or normal peripheral blood, suggesting in vivo activation of T cells by the CD28/B7-1/B7-2 interactions. The irradiated autologous synovium infiltrating T cells notably enhanced IL-1beta, IL-6, and MMP-3 production by the synovial cells. The enhancement of proinflammatory cytokine and MMP-3 production by the synovial cells co-cultured with the T cells was abolished by the addition of CTLA4-Ig, anti-B7-1, and anti-B7-2 monoclonal antibodies. CONCLUSION: These results suggest that cellular interactions between synovium infiltrating T lymphocytes and synovial cells via B7/CD28 pathways are intimately associated with development and exacerbation of inflammation in RA synovial cells.
Adult↗
[Does clinical and medical science for rheumatology hold true as pure life science?].
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Biological Science Disciplines↗
[Left ventricular relaxation in lone atrial fibrillation and atrial fibrillation with heart disease].
Atrial fibrillation with organic heart disease shows a steady value for the time constant of left ventricular isovolumetric relaxation (TC), whereas left ventricular contractility varies from beat to beat. However, there is no report on left ventricular relaxation in lone atrial fibrillation. This study assessed left ventricular relaxation in 5 patients with lone atrial fibrillation, 3 with ischemic heart disease and one with hypertrophic cardiomyopathy. Left ventricular pressure was recorded at 3 msec intervals, with a high fidelity micromanometer-tipped catheter. Maximal positive dP/dt (dP/dtmax) and TC of isovolumetric left ventricular relaxation period [P(t) = (P0-P infinity) exp (-t/TC) + P infinity] were measured as indices of left ventricular contractility and left ventricular relaxation, respectively. Correlation coefficients of dP/dtmax and TC versus the ratio of the preceding to the pre-preceding RR-interval (RR2/RR1) were calculated. A good correlation was found between dP/dtmax and RR2/RR1 in all patients (r = 0.71-0.84, p < 0.0001). No correlation between TC and RR2/RR1 was found in patients with atrial fibrillation with organic heart disease, but a good correlation was found between TC and RR2/RR1 in patients with lone atrial fibrillation (r = 0.74-0.95, p < 0.0001). The correlation between TC and RR2/RR1 is well preserved in lone atrial fibrillation. The mechanism of the variation of TC with the RR2/RR1 interval in lone atrial fibrillation may be similar to the change of TC in postextrasystolic potentiation, which is attributed to the change of intracellular Ca2+ concentration. Absence of correlation between TC and RR2/RR1 interval may indicate that left ventricular relaxation is disturbed in patients with atrial fibrillation with organic heart disease.
Aged↗