Enhanced production and gene expression of IL-5 in bronchial asthma. Possible management of atopic diseases with IL-5 specific gene transcription inhibitor.
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Animals↗
Biomedical subjects
M Suko
Publications and source records attributed to M Suko.
A critical role of IL-2 for the production and gene transcription of IL-5 in allergen-specific human T cell clones.
The role of IL-2 in IL-5 synthesis of human helper T cells was investigated. All of the Der f II (a major allergen of house dust mite)-specific T cell clones established from atopic asthmatic patients produced both IL-2 and IL-4 upon activation (Th0 phenotypes). Recombinant IL-2 induced gene expression and protein synthesis of IL-5 in T cell clones that produced IL-5 upon antigenic stimulation. Human IL-5 promoter/enhancer-luciferase gene construct transfected to T cell clones was clearly transcribed in response to IL-2, indicating that the approximately 500 bp gene segment 5' upstream of the coding region was functionally sufficient for the gene transcription induced by IL-2. IL-2-induced IL-5 synthesis as well as proliferation was dependent on tyrosine kinases. Moreover, IL-5 production by T cell clones stimulated with immobilized anti-CD3 antibody was completely abrogated by anti-IL-2 neutralizing antibody, suggesting that IL-5 (a Th2 cytokine) synthesis of human helper T cells is dependent on IL-2 (a Th1 cytokine). Our present findings clearly demonstrated that IL-2, known as a T cell growth factor, exerts a cytokine promoting activity on T cells. IL-2 produced at the site of allergic inflammation might facilitate eosinophilic inflammation by inducing IL-5 production in T cells.
Allergens↗
A novel phosphodiesterase inhibitor, T-440: possible management of eosinophilic inflammation by down-regulation of interleukin-5 production.
The effect of T-440, a selective type IV phosphodiesterase (PDE IV) inhibitor on interleukin (IL)-5 production by peripheral blood mononuclear cells (PBMCs) of atopic asthmatic subjects was investigated. PBMCs produced IL 5 following challenge with specific allergen in vitro. T-440 suppressed allergen-induced IL-5 production significantly at a concentration of 1 microgram/ml. T-440 inhibited cyclic AMP-phosphodiesterase (PDE) activity in a concentration dependent manner and raised the intracellular cyclic AMP level of PBMCs significantly. Dibutyryl cyclic AMP suppressed IL-5 production by PBMCs in a similar way to T-440, suggesting that the increase of intracellular cyclic AMP caused by T-440 reduces IL-5 production. T-440 may be an effective agent to treat atopic diseases associated with eosinophilic inflammation, e.g. asthma and atopic dermatitis.
3',5'-Cyclic-AMP Phosphodiesterases↗
[Clinical reliability of a new IgE detection system using chemiluminescent enzyme immunoassay named LUMIWARD immunoassay system].
The measurement of allergen-specific IgE antibodies and total IgE was performed with LUMIWARD immunoassay system (chemiluminescent enzyme immunoassay) using 406 serum samples obtained from patients with various allergic diseases and 81 serum samples from normal donors. These were collected by departments of internal medicine, pediatrics, dermatology and otorynolaryngology at eleven institutes in Japan. In addition to a comparative study with CAP RAST, skin tests were also performed to establish a clinical diagnosis. Simultaneous measurements were performed and an excellent correlation with CAP RAST was observed with a concordance rate of 92.6% and correlation coefficient of 0.922. The specificity determined by the normal serum samples was 96.4% for CAP RAST and 96.2% for LUMIWARD. The sensitivity determined by the samples, of which etiological allergens were identified clinically, was 84.8% for CAP RAST and 85.5% for LUMIWARD. Among them, the sensitivity of skin test was 91.8%. The concordance rate with clinical diagnosis was as high as 90.6% and 90.8% for CAP RAST and LUMIWARD. The normal upper limit of total IgE by cumulative 95% value was calculated to be 170 IU/ml for adult subjects. These results indicate the clinical usefulness of the LUMIWARD immunoassay system in evaluating IgE antibodies and total IgE.
Adult↗
Interleukin-5 production by peripheral blood mononuclear cells of asthmatic patients is suppressed by T-440: relation to phosphodiesterase inhibition.
The effect of T-440, a selective type IV phosphodiesterase inhibitor, on cytokine production by peripheral blood mononuclear cells (PBMC) of atopic asthmatics was investigated. T-440 suppressed allergen-induced interleukin (IL)-5 production with a high potency (IC50 = 0.039 microgram/ml) and allergen-induced proliferation of PBMC (IC50 = 0.30 microgram/ml). T-440 also suppressed IL-2, IL-4 and IL-5 production by concanavalin A-activated PBMC in concentration-dependent manner. The IC50 values for the suppression of cytokine synthesis were 0.11 microgram/ml for IL-2, 0.57 microgram/ml for IL-5 and 7.7 micrograms/ml for IL-4. cAMP-elevating agents, such as PGE2, forskolin and dibutyryl cAMP, suppressed IL-2, IL-4 and IL-5 production by concanavalin A-stimulated PBMC in a manner similar to that of T-440. T-440 inhibited cAMP-phosphodiesterase activity and raised the intracellular cAMP level of PBMC in a concentration-dependent manner, suggesting that the increase of intracellular cAMP caused by T-440 results in the reduction of cytokine production. We conclude that T-440 suppressed cytokine production by peripheral T lymphocytes via the protein kinase A pathway and may be an effective modality to treat atopic diseases associated with eosinophilic inflammation.
Adult↗
[Inhibitory effect of ONO-1078, a novel leukotriene receptor antagonist, on human peripheral blood eosinophils].
To determine whether ONO-1078, leukotriene receptor antagonist, inhibits the activation of eosinophils, we investigated the effect of ONO-1078 on the release of leukotriene (LTC4) and eosinophil cationic protein (ECP) from human peripheral blood eosinophils of allergic patients and normal subjects. After preincubation with ONO-1078, eosinophils were incubated with calcium ionophore (A23187). ONO-1078 10(-5) and 10(-6) M inhibited LTC4 release of allergic patients eosinophils and 10(-5)-10(-9) M inhibited LTC4 release of normal subjects eosinophils. ONO-1078, 10(-5) M, also inhibited ECP release of eosinophils obtained from both asthma patients and normal subjects. We think that ONO-1078 may have another pharmacological effect to prevent the activation of human peripheral blood eosinophils by inhibiting LTC4 and ECP release. These results suggest that ONO-1078 might be useful in controlling bronchial asthma.
Asthma↗
IL-5 production by CD4+ T cells of asthmatic patients is suppressed by glucocorticoids and the immunosuppressants FK506 and cyclosporin A.
IL-5 was produced in vitro by peripheral blood mononuclear cells (PBMC) of mite-sensitive atopic patients upon challenge with specific allergen, while PBMC of healthy controls produced essentially no IL-5. Stimuli delivered by the combination of phorbol ester and Ca2+ ionophore induced marked IL-5 production by PBMC obtained from atopic and non-atopic asthmatics, suggesting that both protein kinase C and Ca2+ influx are required for IL-5 production. CD2- or CD4-bearing cell depletion almost completely removed IL-5-producing cells while CD8-bearing cell depletion rather enriched them. These findings indicate that CD4+ T cells are the principal source of IL-5 in PBMC. The capacity of PBMC of atopic asthmatics, non-atopic asthmatics and healthy controls to produce IL-2, IL-4, IL-5 and IFN-gamma was compared, to find that cytokine-producing capacities other than that of IL-5 (IL-2, IL-4 and IFN-gamma) were not significantly different among the three groups. Dexamethasone, FK506 and cyclosporin A suppressed IL-5 production in vitro in a dose-dependent manner. Clear dose-dependent suppression of IL-5 gene expression by FK506 was also observed. Treatment of asthmatic patients with inhaled glucocorticoid (beclomethasone dipropionate) ameliorated clinical symptoms, improved lung function and markedly suppressed IL-5 production by PBMC, suggesting the essential role of IL-5 in the pathogenesis of bronchial asthma and the clinical importance of its regulation.
Adult↗
Effect of fibronectin on the production of leukotriene C4 by eosinophils.
The effect of fibronectin on leukotriene C4 (LTC4) production by eosinophils was examined. Eosinophils obtained from patients with bronchial asthma were cultured for 3 h with or without fibronectin and culture supernatants were assayed for LTC4 by specific enzyme immunoassay. LTC4 was produced in a time- and dose-dependent manner in the presence of fibronectin, and maximum production of LTC4 was observed 3 h after addition of 100 micrograms/ml of fibronectin. These results suggest that eosinophils may be activated by interaction with extracellular matrix proteins, including fibronectin, and play a role in the pathogenesis of bronchial asthma.
Asthma↗
Age-related differential mRNA expression of T cell cytokines in NZB/NZW F1 mice.
The mRNA expression of interleukin (IL)-2, IL-2 receptor-alpha-chain (IL-2R alpha), IL-4 and interferon-gamma (IFN-gamma) in spleen cells from NZB/NZW F1) mice following the stimulation with concanavalin A (Con A) was examined by Northern blot analysis. Kinetic patterns of the mRNA expression after the stimulation were not different between 2-month-old and 6 to 8-month-old B/W F1 mice. However, relative mRNA expression of IL-2 to a cytoskeletal protein, alpha-Tubulin was lower in 6 to 8-month-old B/W F1 mice than in 2-month-old mice. Similar but not significant tendency was observed in IL-2R mRNA expression. In contrast, Relative IL-4 mRNA expression in 6 to 8-month-old B/W F1 mice was significantly higher than that in 2-month-old animals. On the other hand, no apparent change was observed in IFN-gamma mRNA expression. Flow cytometric analysis indicated that there was no apparent difference in proportion of L3T4 positive T cells in spleen cells from 2 and 6 to 8-month-old B/W F1 mice. These results suggest that mRNA expression of IL-2 and IL-4 differentially changes with aging in autoimmune B/W F1 mice.
Age Factors↗
[A case of sarcoidosis with right pneumothorax and multiple cavities in both lung fields].
A 26-year-old man was admitted to our hospital for evaluation of cavitary lesions on his chest X-ray film. Chest CT and conventional tomograms showed multiple cavities in both lung fields, as well as hilar and mediastinal lymphadenopathy. He had uveitis and the laboratory data showed a high level of angiotensin converting enzyme in the serum. Histological findings of the specimen obtained by transbronchial lung biopsy showed non-caseating epithelioid cell granuloma, consistent with sarcoidosis. Corticosteroid therapy (prednisolone 40 mg/day) resulted in reduction of the cavitary lesions and the lymphadenopathy. Negative bacteriological studies and the clinical course strongly suggested primary cavitation, a relatively rare form of pulmonary parenchymal involvement in sarcoidosis.
Adult↗
Accumulation of multiple T cell clonotypes in lungs of healthy individuals and patients with pulmonary sarcoidosis.
T cell accumulation and activation in lung may play a major role in the pathogenesis of immunologic lung diseases such as sarcoidosis. Using the combination of RT-PCR and subsequent single-strand conformation polymorphism analysis, we examined T cell clonality in lung and peripheral blood of healthy individuals (n = 5) and patients with active pulmonary sarcoidosis (n = 7). RNA was extracted from PBLs and bronchoalveolar lavage fluid cells, and converted to cDNA. PCR was performed using a set of V beta-C beta primers (V beta 1-20). Products were denatured and electrophoresed in nondenaturing 5% polyacrylamide gel. The existence of a distinct T cell clonotype was detected as a band on a smear. In both groups T cells in PBLs showed a number of clones that expanded. A significantly greater number of clones was detected in BAL compared with PBL in both groups (normal: 25.3 +/- 7.2 in PBL vs 62.8 +/- 5.2 in lung; sarcoid: 25.0 +/- 6.2 in PBL vs 90.0 +/- 6.6 in lung, mean value +/- SEM). In sarcoid lung greater numbers of clones were detected than in lungs of healthy controls (p < 0.012). These clonal expansions were observed over all the 20 V beta families examined, and were not restricted to certain V beta families. These results suggest that there are clonal expansions even in normal lung, and that in sarcoidosis, apparently, additional T cell clones using multiple V beta segments might be activated and accumulated at the site of the disease.
Adult↗
Regulation of interleukin-5 production by peripheral blood mononuclear cells from atopic patients with FK506, cyclosporin A and glucocorticoid.
Upon stimulation with phorbol ester and ionomycin, peripheral blood mononuclear cells (PBMC) of atopic patients with moderate eosinophilia produced significantly higher amounts of IL-5 compared to that of normal subjects. This finding renders further support to the notion that T cell-eosinophilic inflammation plays a central role in allergic disorders. IL-5 induction in vitro was completely inhibited by immunosuppressant FK506, cyclosporin A and dexamethasone. FK506 applied in vivo effectively suppressed clinical symptoms of atopic dermatitis and IL-5 production of PBMC. FK506 and cyclosporin A may become a better therapeutic modality against allergic diseases.
Administration, Topical↗
Effectiveness of disodium cromoglycate in food-dependent, exercise-induced anaphylaxis: a case report.
An 18-year-old girl experienced anaphylactic reactions three times and frequent urticaria with exercise after meals that included wheat. Allergy evaluation showed a strong prick test reaction to wheat, and RAST score was 2 for wheat. Exercise provoked a decrease of FEV1 of 7.4% and increase of plasma histamine with no symptoms. Exercise after eating wheat provoked an FEV1 decrease of more than 18.7%, further increase of plasma histamine, urticaria and mild dyspnea. Oral administration of disodium cromoglycate before ingestion of bread and exercise challenge caused a maximal FEV1 increase of 6%, no increase of the plasma histamine, and no symptoms.
Adolescent↗
[The potential role and mechanism of leukotriene and platelet-activating factor in allergic disease].
Eosinophilic accumulation in the airway is a prominent feature in patients with bronchial asthma (chronic desquamative eosinophilic bronchitis). Recently, arachidonic acid metabolite such as leukotriene, 15-HETE and PAF are proved to play an essential role as chemical mediators in the pathogenesis of bronchial asthma. A close relation is found between eosinophils activation and those mediators. The bronchoconstrictive leukotriene (LT C4, D4, E4) are generated mainly from eosinophils and mast cells, while the chemoattractive LTB4 is produced from neutrophils. Platelet activating factor (PAF) is postulated as a causative mediator of the eosinophilic airway inflammation and bronchial hyperresponsiveness because PAF attracts and activates preferentially eosinophils. Evidence that eosinophils have ability to produce PAF like other inflammatory cells suggests an autocrine mechanisms of the eosinophil activation by PAF.
Asthma↗
Hypersensitivity pneumonitis in athymic nude mice. Additional evidence of T cell dependency.
We previously demonstrated that C57 Black/6 mice develop lung lesions similar to human hypersensitivity pneumonitis (HP) by repeated transnasal administration of Thermoactinomyces vulgaris (Tv) antigen. To elucidate the role of T cells in the development of this disease, Tv antigen (90 micrograms/day) was transnasally administered to athymic nude C57 Black/nu/nu (nu) mice and their littermates (+/nu) three times a week for 3 wk. The nude mice developed minimal lung lesions, whereas their thymus-intact littermates (+/nu) showed changes equivalent to those in C57 Black/6. Changes in local inflammatory cell responses were evaluated by bronchoalveolar lavage, and increases in the numbers of lymphocytes and macrophages were significantly less severe in the nude mice than in the +/nu mice. Interestingly, the increase in polymorphonuclear leukocytes 6 h after the last antigen inoculation was equivalently seen in both groups. When spleen-derived T cells (more than 95% Thy-1.2+) from the sensitized +/nu mice were adoptively transferred to nude mice, the HP-like lesions in the recipients were found after Tv antigen challenge. These results suggest that Thy-1.2+ T cell-mediated immunity was necessary for the development of HP in this murine model.
Alveolitis, Extrinsic Allergic↗
[A case of hypersensitivity pneumonitis in which serum specific antibodies for three species of isocyanate molecules were demonstrated].
A 64-year-old male was admitted to our hospital with complaints of the development of high fever, cough and dyspnea 5-6 hours after painting automobiles. His chest X-ray film showed interstitial shadows in both lungs. Pulmonary function test demonstrated reduction of diffusion capacity; and blood gas analysis demonstrated hypoxemia and an increase in alveolar-arterial oxygen tension difference. Marked lymphocytosis and a striking decrease in CD4/CD8 ratio were observed in the bronchoalveolar lavage fluid. Transbronchial lung biopsy specimens showed alveolitis and Masson's bodies. We suspected that the patient was suffering from hypersensitivity pneumonitis induced by isocyanates contained in the urethane paint he used. Immunological studies were performed using chemical compounds of three species of isocyanate molecules (TDI, MDI, HDI) and human serum albumin (HSA). The results were as follows: skin tests were positive for TDI-HSA and MDI-HSA; lymphocyte-stimulation tests on peripheral blood were positive for TDI-HSA; precipitation reaction was negative for all the isocyanates studies; enzyme-linked immunosorbent assay (ELISA) demonstrated the existence of specific IgG antibodies for TDI, MDI and HDI; inhalation challenge test by TDI-HSA was negative, but environmental provocation was considered to be positive. We diagnosed his pulmonary disorder as hypersensitivity pneumonitis due to isocyanates. Type III and Type IV allergic reactions of Gell-Coombs were suggested to be involved in the pathogenesis, however, there remains the possibility that the instability of isocyanate compounds as antigen modified the results of our immunological studies.
Alveolitis, Extrinsic Allergic↗
Is a trypsin-like protease of mites a Der f III allergen?
A trypsin-like protease was purified from mite (Dermatophagoides farinae) fecal extract. In SDS-PAGE, the mite trypsin-like protease showed a single band at 34 kD. The purified trypsin-like protease possessed potent allergenic activity. Both the twenty N-terminal amino acid sequence and the amino acid composition of the purified protease were very similar to those of Der f III. These data strongly suggest that the trypsin-like protease in the mite is a Der f III allergen.
Allergens↗
[A case of asymptomatic endobronchial lipoma followed for 4 years].
Bronchoscopy was performed on a 68-year-old male patient with pulmonary tuberculosis, and revealed a yellow smooth polypoid tumor in the lumen of the left upper division bronchus. The histopathological diagnosis of the biopsy specimen was endobronchial lipoma. Since the patient did not have any symptoms due to the lipoma, we performed treatment for tuberculosis and continued careful observation of the tumor. During the subsequent 4 years, the patient developed no complications such as obstructive pneumonia, and the size of the tumor under bronchoscopic observation did not change. Endobronchial lipoma is a very rare benign tumor. Almost all reported cases have undergone operation or endoscopic surgery. This case is the first that was followed over 4 years without surgical procedure. The findings of follow-up bronchoscopic examination suggest that the growth rate of endobronchial lipoma is very slow. Furthermore, we reviewed 36 cases of endobronchial lipoma in the Japanese literature, including our case. Smoking seems to have a strong relation to the occurrence of the tumor. It is noteworthy that 6 cases had separate malignancies, but the direct relationship between endobronchial lipoma and such malignancies is unclear.
Aged↗