Yoko Nishizaki

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.

Cellular and molecular mechanisms of IL-5 synthesis in atopic diseases: A study with allergen-specific human helper T cells ☆ ☆☆ ★

BACKGROUND Cytokines produced by helper T cells are intimately involved in chronic allergic diseases associated with eosinophilic inflammation. OBJECTIVE We investigated the production of IL-5, a potent growth factor and chemotactic factor for eosinophils, by CD4+ T lymphocytes in patients with asthma. METHODS Allergen-specific T cell clones and T cell hybridomas were established from the peripheral blood lymphocytes of patients with asthma, and the responses to various stimuli were determined. RESULTS After nonspecific stimulation, IL-5 production by CD4+ T cells from both atopic and nonatopic subjects with asthma was significantly enhanced compared with that by cells from healthy controls. Peripheral blood mononuclear cells from atopic asthma patients both proliferated and produced IL-5 after incubation with mite allergen, suggesting that mite-specific helper T cells were involved in the eosinophilic inflammation of atopic asthma. A human IL-5 promoter/enhancer luciferase gene construct transfected into IL-5-producing T cell clones was clearly transcribed after stimulation, indicating that the 515 base pair IL-5 gene segment upstream of the coding region was sufficient to respond to activating signals in human helper T cells. The same gene segment was not transcribed in IL-5-nonproducing T cell clones, suggesting that human T cell IL-5 synthesis is regulated at the transcriptional level. Experiments with T cell hybridomas confirmed these findings and suggested that a unique transcription factor may be essential for human IL-5 gene transcription. CONCLUSION Enhanced IL-5 production by helper T cells seems to cause the eosinophilic inflammation of both atopic and nonatopic asthma. Elucidation of IL-5-specific regulatory mechanisms may facilitate the development of novel treatments for allergic diseases associated with eosinophilic inflammation.

Allergen-Specific Human T Cell Clones Produce lnterleukin-5 upon Stimulation with the Th1 Cytokine lnterleukin-2

CD4+ T cell clones specific for Der fII (a major allergen of the house dust mite) were established from peripheral blood mononuclear cells of atopic patients. All of the T cell clones were classified as having the Th0 phenotype, since they produced both interleukin (IL)-2 and IL-4 upon stimulation. Some of the clones produced IL-5 upon antigenic stimulation. Human recombinant IL-2 induced these T cell clones to express IL-5 mRNA and produce IL-5 protein in a dose-dependent manner. IL-2 did not induce IL-4 production, indicating a discrete signal requirement for IL-4 versus IL-5 production by T cells. Moreover, IL-5 production induced by immobilized anti-CD3 monoclonal antibody was completely suppressed by the addition of anti-IL-2 monoclonal antibody, suggesting that IL-5 production, designated as a Th2-type immune response, is dependent on IL-2, a Thl cytokine. IL-2 produced at the site of allergic inflammation may contribute to IL-5 production by T cells in vivo.

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.

Enhanced Production and Gene Expression of IL-5 in Bronchial Asthma

Infiltration of various inflammatory cells into the bronchial mucosa and submucosa is a prominent pathological feature of bronchial asthma.1–3 Persistent mucosal inflammation, particularly epithelial damage caused by eosinophil-derived products, is believed to contribute to the pathogenesis of bronchial hypersensitivity.4–7 Inhalation of a relevant allergen results in an early asthmatic reaction (EAR) that subsides within 1 to 2 hours. In 40–60% of patients, this early reaction is followed after 6 to 10 hours by a late asthmatic reaction (LAR), which usually subsides during the next 1 to 2 days.8 Accumulating evidence suggests that LAR is a consequence of eosinophilic inflammation in the lung induced by a T cell cytokine, interleukin 5 (IL-5).9–15