Tumour necrosis factor-related apoptosis-inducing ligand expression in atopic dermatitis.
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Apoptosis↗
Biomedical subjects
H Ushio
Publications and source records attributed to H Ushio.
Transforming growth factor-beta1 suppresses atopic dermatitis-like skin lesions in NC/Nga mice.
BACKGROUND: Atopic dermatitis is a chronic, relapsing inflammatory disorder characterized by pruritic and eczematous skin lesions. Transforming growth factor (TGF)-beta1 has been implicated in the suppression of inflammatory responses. OBJECTIVE: The purpose of this study is to determine whether TGF-beta1 suppresses skin lesions in a mouse model of atopic dermatitis. METHODS: We used the NC/Nga strain of mice as an in vivo model of atopic dermatitis. The effects of exogenous TGF-beta1 on atopic dermatitis-like skin lesions in NC/Nga mice were evaluated clinically, histologically and immunologically. RESULTS: Subcutaneous injection of recombinant TGF-beta1 macroscopically suppressed eczematous skin lesions in NC/Nga mice associated with reduced serum immunoglobulin E (IgE) levels. Histological analysis showed that TGF-beta1 significantly inhibited the infiltration of inflammatory cells such as mast cells and eosinophils into the skin of NC/Nga mice. Spontaneous interferon (IFN)-gamma production from splenocytes of NC/Nga mice was down-regulated by the treatment with TGF-beta1 and neutralizing antibody against IFN-gamma inhibited skin lesions in NC/Nga mice. The inhibitory effect of TGF-beta1 on the skin lesions lasted at least 1 week after cessation of the treatment. CONCLUSION: These findings indicate that TGF-beta1 suppressed atopic dermatitis-like skin lesions in NC/Nga mice at least in part through down-regulation of IFN-gamma. These results suggest that TGF-beta1 may have a therapeutic potential for atopic dermatitis.
Animals↗
Optimized conditions of bio-mimetic artificial membrane permeation assay.
Effects of pH and co-solvents on the bio-mimetic artificial membrane permeation assay were investigated to determine the optimal conditions for the prediction of oral absorption. The permeability (P(am)) of 33 structurally diverse drugs to the PC/PE/PS/PI/CHO/1,7-octadiene membrane system (bio-mimetic lipid (BML) membrane) was measured at pH 5.5, 6.5, and 7.4. The pH dependence of P(am) was in accordance with the pH partition theory. The better prediction of oral absorption (fraction of a dose absorbed) was shown under the pH 5.5 condition (r=0.866, n=25) and/or pH 6.5 (r=0.865, n=28), rather than pH 7.4 (r=0.767, n=24). Then, the appropriate conditions for determining the permeability of poorly soluble compounds were examined. Dimethysulfoxide (DMSO), ethanol (EtOH) and polyoxyethyleneglycol 400 (PEG 400) were added up to 30% to the transport medium as solubilizers. DMSO, EtOH and PEG 400 decreased P(am) of hydrocortisone and propranolol. For example, DMSO (30%) decreased P(am) of hydrocortisone by 60% and by 70% in the case of propranolol. DMSO and PEG 400 also decreased P(am) of ketoprofen. In contrast, EtOH produced an opposite effect on permeability, i.e. an increased P(am) of ketoprofen. Therefore, the high concentration of these co-solvents could lead to the under- or overestimation of drug permeability.
Algorithms↗
Protective roles of mast cells against enterobacterial infection are mediated by Toll-like receptor 4.
Toll-like receptors (TLRs) are mammalian homologues of the Drosophila Toll receptors and are thought to have roles in innate recognition of bacteria. We demonstrated that TLR 2, 4, 6, and 8 but not TLR5 were expressed on mouse bone marrow-derived mast cells (BMMCs). Using BMMCs from the genetically TLR4-mutated strain C3H/HeJ, we demonstrated that functional TLR4 was required for a full responsiveness of BMMCs to produce inflammatory cytokines (IL-1beta, TNF-alpha, IL-6, and IL-13) by LPS stimulation. TLR4-mediated stimulation of mast cells by LPS was followed by activation of NF-kappaB but not by stress-activated protein kinase/c-Jun NH2-terminal kinase signaling. In addition, in the cecal ligation and puncture-induced acute septic peritonitis model, we demonstrated that genetically mast cell-deficient W/W(v) mice that were reconstituted with TLR4-mutated BMMCs had significantly higher mortality than W/W(v) mice reconstituted with TLR4-intact BMMCs. Higher mortality of TLR4-mutated BMMC-reconstituted W/W(v) mice was well correlated with defective neutrophil recruitment and production of proinflammatory cytokines in the peritoneal cavity. Taken together, these observations provide definitive evidence that mast cells play important roles in exerting the innate immunity by releasing inflammatory cytokines and recruitment of neutrophils after recognition of enterobacteria through TLR4 on mast cells.
Acute Disease↗
Induction of the imbalance of helper T-cell functions in mice exposed to diesel exhaust.
Administration of diesel exhaust particles (DEP) increases antigen-specific IgE production and IgE-secreting cells, and induces Th2-type cytokine profiles in the airway in mice and humans. To determine the early effects of diesel exhaust (DE) inhalation on the cytokine production profile, BALB/c mice were exposed to 0 (controls) and 1.0 mg/m3 DE inhalation for 4 weeks. Intraperitoneal sensitization with ovalbumin (OVA) was conducted immediately before DE inhalation. Mice were treated with anti-CD4 or anti-CD8 mAb 1 day before and after the sensitization. On day 21, these mice were boosted with OVA and blood; bronchoalveolar lavage (BAL) fluid, and spleens were collected on day 28. In BAL fluid, both TNFalpha and IL-10 production in DE-exposed and control mice remained basically the same. IL-6 production in the anti-CD4 treatment group of DE-exposed mice, however, significantly increased compared with that of the controls. In vitro antigen-stimulated interleukin-4 (IL-4) and -10 (IL-10) production in spleen cells of exposed mice were not affected by low-dose DE inhalation. In vitro interferon (IFN)-gamma production in the anti-CD4 treated group of exposed mice decreased markedly. Although anti-OVA IgE production in the plasma of sham-treated mice exposed to DE was the same level as for controls, anti-CD4 mAb treatment in DE-exposed mice significantly reduced IgE production compared to controls. In anti-OVA IgG1 production, anti-CD4 or anti-CD8 mAb treatment in DE-exposed groups also significantly reduced. Anti-OVA IgG2a production was reduced by treatment with anti-CD4 mAb, but increased by anti-CD8 mAb treatment in DE-exposed mice. Low dose DE inhalation is thus shown to adversely affect the cytokine and antibody production in mice by altering CD4+ and CD8+ T-cell functions.
Administration, Inhalation↗
Seasonal variation of phosphatidylcholine hydroperoxides in blood of sweet smelt Plecoglossus altivelis.
Sweet smelt was reared at two fishery experimental stations for 5 months from June to October. Every 2 weeks blood was collected from the caudal vessels and, subsequently, the phosphatidylcholine hydroperoxide contents and the fatty acid compositions in the blood were determined by high-performance liquid chromatography and gas chromatography, respectively. The seasonal variation of the contents of accumulated hydroperoxides and fatty acids in the sweet smelt blood were observed in both experimental stations. Sweet smelt started performance of cucumber-like or watermelon-like aroma in the middle of July and the aroma was enhanced in August. The content of phosphatidylcholine hydroperoxides and the amount of total fatty acid in the fish blood, in terms of possible precursors of volatile compounds, were also extremely high in the same period. According to lipid peroxidation mechanisms, the strong characteristic aroma of sweet smelt during July to August might be due to the high contents of accumulated lipid hydroperoxides and polyunsaturated fatty acids in their tissues.
Animals↗
Sphingomonas cloacae sp. nov., a nonylphenol-degrading bacterium isolated from wastewater of a sewage-treatment plant in Tokyo.
A nonylphenol-assimilating bacterium isolated at a sewage-treatment plant in Tokyo was studied phenotypically, genotypically and phylogenetically. Analysis of the 16S rDNA sequence, the G+C content of the DNA (63 mol%) and the isoprenoid quinone composition, as well as the presence of sphingoglycolipid and the whole-cell fatty acid profile, revealed that the isolate is a member of the genus Sphingomonas. However, the sequence similarity of the 16S rDNA with that of known Sphingomonas spp. was found to be at most 96%, implying that the isolate is distinctive. Furthermore, the results of DNA-DNA hybridization experiments and its physiological characteristics clearly indicated that the isolate represents a new Sphingomonas species, for which the name Sphingomonas cloacae is proposed; strain S-3T (= JCM 10874T = IAM 14885) is the type strain.
Bacterial Typing Techniques↗
Roles of CD4+ and CD8+ T cells in adjuvant activity of diesel exhaust particles in mice.
Through an imbalance in Th1 and Th2 cytokine profiles, diesel exhaust particles (DEP) are thought to induce Th2-dominated IgE and IgG1 production. However, the roles of CD4+ and CD8+ T-cell subtypes in the increased immune responses to antigen in mice exposed to DEP are unclear. In the present study, we investigated whether treatment with anti-CD4 or anti-CD8 mAb abrogated the adjuvant activity of DEP. On day -1 and day 1, each group of mice was injected intraperitoneally with anti-CD4, anti-CD8, or rat IgG (vehicle). On day 0, the mice were immunized with ovalbumin (OVA) or OVA plus DEP. After 3 weeks, each mouse was boosted with 10 microg of OVA alone. On day 7 after the first injection with OVA+DEP or OVA alone, the numbers of total, IA+, CD80+/IA+ and CD86+/IA+ cells in peritoneal exudate cells (PEC) were higher in OVA+DEP-immunized mice than in OVA-immunized mice. Depletion of CD8+ cells resulted in a modulation of the production of granulocyte-macrophage colony-stimulating factor, IL-12 and PGE(2) in peritoneal exudate fluid from OVA+DEP-immunized mice. On day 28, DEP injection markedly increased IL-4 production in the culture supernatants of spleen cells from CD4+ or CD8+-depleted mice. Depletion of CD8+ cells in OVA+DEP-immunized mice resulted in a decrease in IFN-gamma production compared with that in OVA-immunized mice. Adjuvant activity of DEP was observed in anti-OVA IgE, anti-OVA IgG1, anti-OVA IgG3, and total IgE production. Depletion of CD4+ T cells abrogated the adjuvant effect of DEP on anti-OVA IgE, and anti-OVA IgG1 production in plasma. However, depletion of CD8+ T cell inhibited the upregulated anti-OVA IgG3 production. These findings suggest that DEP injection may affect not only the function of CD4+ cells but also that of CD8+ T-cell subsets to modulate the synthesis of proinflammatory cytokine in PEC and type-1 and type-2 cytokine production in spleens.
Adjuvants, Immunologic↗
High throughput prediction of oral absorption: improvement of the composition of the lipid solution used in parallel artificial membrane permeation assay.
The purpose of the present study was to improve the composition of the lipid solution used in parallel artificial membrane permeation assay for the precise prediction of oral absorption. We modified the composition of lipid solution, which was used to make a lipid membrane on the filter support. First, we changed the chain length of organic solvent (PC/alkyldienes [C7-C10]). A negative charge was then added to the membrane to mimic the intestinal membrane (PC/stearic acid/1,7-octadiene and PC/PE/PS/PI/cholesterol/1,7-octadiene). Finally, we examined the predictability of the PC/PE/PS/PI/CHO/1,7-octadiene membrane using structurally diverse compounds. Permeability coefficients of tested compounds were increased as the chain length of alkyldiene became shorter. The addition of a negative charge to the membrane increased the permeability of the basic compounds. However, the negatively charged membrane with stearic acid showed different permeability profiles from PC/PE/PS/PI/CHO. The predictability of the PC/PE/PS/PI/CHO/1,7-octadiene membrane was adequate (r = 0.858, n = 31) for use during the early stages of the drug discovery/development process.
Absorption↗
The effects of perinatal exposure to low doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin on immune organs in rats.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is revealed to exert diverse biological effects including immunotoxicity, mainly by inadvertently activating the transcription factor arylhydrocarbon receptor (AhR). In the present study, the developmental effects of perinatal exposure to low doses of TCDD on the major immune organs of offspring, thymus and spleen, were investigated focusing on weaning time (postnatal day (PND) 21), puberty (PND 49) and adulthood (PND 120) in male rats. Concurrently, TCDD contents in those organs were measured with a high-resolution gas chromatography-mass spectrometry (GC/MS). In the thymus and spleen, CYP1A1 mRNA induction, the sensitive reaction caused by activation of AhR, was also measured in order to examine whether perinatally administered TCDD can elicit gene expressions in these organs. When pregnant dams were administered a single oral dose of 12.5-800 ng TCDD/kg body weight on gestation day (GD) 15, the weights of the thymus and spleen of the offspring did not differ from those of control animals throughout the experiments. The thymus and spleen maternally exposed to 800 ng TCDD/kg contained 102.0 and 62.7 pg TCDD/g tissue on PND 21, respectively, and the amounts decreased thereafter. In the thymus, dose-dependent CYP1A1 mRNA induction was clearly observed by maternal exposure to 50-800 ng TCDD/kg on PND 5. The induction was gradually decreased on PND 21 and 49. On the other hand, CYP1A1 mRNA induction in the spleen was very weak. In these thymi, no reproducible change was observed by TCDD exposure in cell number and cellular population defined by CD4 and CD8 molecules at any time. In contrast, splenocyte number was shown to decrease by maternal exposure to 12.5-800 ng TCDD/kg in a dose-dependent manner on PND 49. The alteration in spleen cellularity by TCDD was not detected on PND 21 or 120. These results clarified that perinatal exposure to low doses of TCDD affects the immune organs, which is apparent in spleen around puberty and likely to be hardly relevant to AhR-dependent gene expressions.
Animals↗
Quantitative structure-intestinal permeability relationship of benzamidine analogue thrombin inhibitor.
The intestinal permeability of benzamidine analogue thrombin inhibitor is correlated with molecular volume, lipophilicity (calculated log P and IAM column capacity factor), hydrogen bond acidity/basicity and dipolarity.
Benzamidines↗
Alterations of thymocyte development, thymic emigrants and peripheral T cell population in rats exposed to 2,3,7, 8-tetrachlorodibenzo-p-dioxin.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exerts diverse biological effects by activating the cytosolic transcription factor, arylhydrocarbon receptor (AhR), which translocates to nuclei by TCDD binding and induces gene expressions. Among the well known-adverse effects of TCDD is thymus atrophy. In thymus atrophy, TCDD alters the proliferation as well as the differentiation of immature thymocytes. Previous studies on the effects of TCDD on thymocyte development were primarily carried out with high doses of TCDD. The present study investigates the effects of lower doses of TCDD (1 or 2 microg TCDD/kg by gavage) on thymocyte development, and furthermore, their sequential consequences on the peripheral T cell repertoire. Seven days after treatment with 1 or 2 microg TCDD/kg, the expression of CYP1A1 mRNA, one of the sensitive responses caused by the binding of TCDD to AhR, was detected in the thymus of rats. Thymus weights and thymus cell numbers decreased in TCDD-treated rats in a dose-dependent manner. The ratios of CD4 single-positive (SP) cells/CD8 SP cells were significantly reduced by TCDD exposure, indicating that the maturation of CD4(+)CD8(+) double-positive (DP) cells was skewed toward CD8 SP cells. These changes in the thymus were parallel to those previously observed with high doses of TCDD exposure. However, the specific reduction of DP cells reported in previous studies with high doses of TCDD was not detected in the present study. On the other hand, the skewing of mature CD4/CD8 T cell ratio in thymocytes by TCDD was not reflected in mesenteric lymph node (LN) lymphocytes, where the proportion of CD8 T cells was rather lowered by TCDD with a significant difference at 1 microg TCDD/kg. In LN lymphocytes, the percentage of recent thymic emigrants (RTEs), defined by the surface markers of Thy1(+)CD45RC(-), was shown to be significantly reduced by exposure to 1 and 2 microg TCDD/kg. T cell supply from the thymus has a crucial role in keeping the diversity of the T cell repertoire. The results of the present study indicated that lower doses of TCDD affect thymocyte development, especially differentiation, and reduce the proportion of RTE in LN, which may cause immunosuppression by reducing the variety of the T cell receptor repertoire.
Animals↗
Profile of a nonylphenol-degrading microflora and its potential for bioremedial applications.
Nonylphenol (NP) is an important intermediate in the production of various commercial and industrial materials, but is also known as a ubiquitous pollutant in urban aquatic environments. We recently studied the NP-degrading activities of microflora in several aquatic environments, and found a notable degrading activity for wastewater from a sewage treatment plant in Tokyo. This result led us to isolate NP-degrading microbes and identify biodegradation products. Using conventional plate culture techniques and molecular biological methods, Pseudomonas and Sphingomonas species, which are known for their degradation activities of many aromatic compounds, have been isolated. But it has also been found that Sphingomonas sp. (S-strain) is necessary and sufficient for the degradation of NP. Although the role of Pseudomonas sp. (P-strain) remains unclear, P-strain seems to provide some co-nutrients for the growth of S-strain. The degradation products were analyzed by GC/MS and NMR. More than 95% of NP was degraded within 10 days and aromatic compounds other than NP were not found, suggesting that the phenolic part of NP was completely degraded. We also examined the potential of S-strain for bioremedial applications. S-strain cells immobilized on chitosan or alginate beads retain their NP-degrading activity in flask-scale experiments. Furthermore, the chitosan-bound cells in a lab-scale bioreactor have been found to be persistent for repeated use, suggesting that S-strain is applicable to the treatment of NP-contaminated wastewater.
Base Sequence↗
[Mastocytosis].
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Diagnosis, Differential↗
Effect of environmental pollutants on the production of pro-inflammatory cytokines by normal human dermal keratinocytes.
The effect of the environmental pollutants, diesel exhaust particles (DEP) and formaldehyde (FA), on the production of pro-inflammatory cytokines (interleukin (IL)-1alpha, IL-1beta, tumor necrosis factor (TNF)-alpha and IL-8) by normal human dermal keratinocytes (hKCs) was investigated. Normal hKCs were incubated with various concentrations of DEP (0.4, 0.8, 4, or 20 microg/ml) or FA (0.25, 0.5, 1, or 5 microg/ml), and cytokine production was then determined by enzyme-linked immunosorbent assay (ELISA). DEP (20 microg/ml) induced IL-1beta production without altering cell growth. The increased production of IL-1beta induced by this concentration of DEP was further enhanced by the presence of phorbol 12-myristate 13-acetate (PMA), although PMA alone did not affect the levels of IL-1beta. IL-8 production was also increased by DEP (0.4 and 0.8 microg/ml), which is consistent with the results that these concentrations of DEP increased the number of cells significantly after 72 h incubation. Although FA alone did not stimulate the production of IL-1beta or IL-8 by keratinocytes, FA (0.5 microg/ml and 5 microg/ml) significantly increased IL-8 and IL-1beta production, respectively, in cells stimulated with PMA. IL-1alpha production was not modulated by FA or DEP even in the presence of PMA. TNF-alpha was produced by unstimulated keratinocytes at barely detectable levels after 48 h incubation. Although basal levels of TNF-alpha in the culture supernatants were increased after stimulation with PMA, neither pollutant alone nor combination with PMA affected the levels of TNF-alpha. These in vitro findings suggest that environmental pollutants may act as modulating factors of cutaneous inflammation by affecting the ability of keratinocytes to release pro-inflammatory cytokines.
Cells, Cultured↗
IgE hyperproduction through enhanced tyrosine phosphorylation of Janus kinase 3 in NC/Nga mice, a model for human atopic dermatitis.
IgE hyperproduction frequently observed in patients with atopic dermatitis (AD) may greatly contribute to the pathogenesis of AD, but its mechanisms are still unclear. NC/Nga mice raised in nonsterile circumstances spontaneously suffered from AD-like skin lesions with elevation of plasma IgE levels. We investigated mechanisms of the IgE hyperproduction in NC/Nga mice. Splenic T cells from SPF NC/Nga mice had a level of CD40 ligand (CD40L) expression comparable to that of BALB/c mice. Although there was no difference in the expression of CD40 on B cells between NC/Nga and BALB/c mice, B cells of NC/Nga mice produced much more IgE in the presence of soluble CD40L and IL-4. The stimulation with CD40L and/or IL-4 resulted in tyrosine phosphorylation of Janus kinase 3 (JAK3) in B cells, which was more strongly inducible in NC/Nga mice than in BALB/c mice. In B cells isolated from PBMC of AD patients with high serum IgE levels, JAK3 was constitutively phosphorylated at the tyrosine residue, and its phosphorylation was enhanced by the treatment with CD40L and/or IL-4 as was that in splenic B cells of NC/Nga mice with dermatitis and high IgE levels. Thus, it is suggested that constitutive and enhanced JAK3 phosphorylation in B cells highly sensitive to CD40L and IL-4 may be attributable to IgE hyperproduction in NC/Nga mice and patients with AD.
Aluminum Hydroxide↗
Proportion of geometrical hydroperoxide isomers generated by radical oxidation of methyl linoleate in homogeneous solution and in aqueous emulsion.
The proportion of geometrical hydroperoxide isomers generated by aerobic oxidation of methyl linoleate (18:2 Me) in either aqueous emulsion consisting of Tris-HCl buffer (pH 7.4) or in a homogeneous dichloromethane solution was determined to understand the mechanism of lipid oxidation in different reaction systems. Four geometrical isomers were generated after oxidation of 18:2 Me in dichloromethane: methyl 13-hydroperoxy-cis-9, trans-11-octadecadienoate, methyl 13-hydroperoxy-trans-9,trans-11-octadecadienoate, methyl 9-hydroperoxy-trans-10,cis-12-octadecadienoate, and methyl 9-hydroperoxy-trans-10, trans-12-octadecadienoate in the ratios of 1:4:1:4, respectively. The ratios between each isomer did not change until the peroxide value (PV) increased to 58 meq/kg. Oxidation of 18:2 Me in aqueous emulsion yielded the same geometrical isomers of hydroperoxide. However, the ratios were different: 3:2:3:2 until the PV increased to 110 meq/kg. Predominant (60%) formation of trans,trans hydroperoxide isomers was obtained in the oxidation of a mixture of 18:2 Me and methyl laurate (12:0 Me). These results are interpreted to reflect the importance of the concentration of hydrogen atom-donating equivalents to the kinetic preference for different products. The high effective concentration of hydrogen donors in the oxidation of 18:2 Me in emulsions favored the formation of the less stable cis,trans isomers. The lower concentration of hydrogen donor in the dichloromethane solution effectively slowed hydrogen donation and led to the strong preference for the more stable trans,trans isomers. This interpretation was further tested by preparing emulsions of 18:2 Me and 12:0 Me to dilute concentration of hydrogen-donating species using the nonhydrogen-donating 12:0 Me. Consistent with the proposed hypothesis, the proportion of trans,trans isomers increased as a result of 12:0 Me addition.
Chromatography, High Pressure Liquid↗
Subcellular distribution of tetrodotoxin in puffer fish liver.
The liver homogenate of puffer fish was fractionated into blood cell, nuclear, mitochondrial, microsomal and cytosol fractions by the differential centrifugation method. All the five fractions were toxic to mice, although the toxin amount was significantly high in the cytosol fraction. Analyses by HPLC and LC-FABMS demonstrated that tetrodotoxin is the major toxic principle in each fraction. These results reveal that tetrodotoxin is widely distributed in organelles in liver cells, though predominantly in the cytosol fraction.
Adult↗