Two distinct pathways of interleukin-5 synthesis in allergen-specific human T-cell clones are suppressed by glucocorticoids.
Glucocorticoids (GC) have long been used as the most effective agents for the treatment of allergic diseases accompanied by eosinophilia such as chronic asthma and atopic dermatitis. The development of chronic eosinophilic inflammation is dependent on interleukin-5 (IL-5), a selective eosinophil-activating factor, produced by helper T cells. To delineate the regulatory mechanisms of human IL-5 synthesis, we established allergen-specific CD4+ T-cell clones from asthmatic patients. GC efficiently suppressed IL-5 synthesis of T-cell clones activated via either T-cell receptor (TCR) or IL-2 receptor (IL-2R). Induction of IL-5 mRNA upon TCR and IL-2R stimulation was totally inhibited by dexamethasone. Human IL-5 promoter/enhancer-luciferase gene construct transfected to T-cell clones was transcribed on either TCR or IL-2R stimulation and was clearly downregulated by dexamethasone, indicating that the approximately 500-bp human IL-5 gene segment located 5' upstream of the coding region contains activation-inducible enhancer elements responsible for the regulation by GC. Electrophoretic mobility shift assay analysis suggested that AP-1 and NF-kappaB are among the possible targets of GC actions on TCR-stimulated T cells. NF-AT and NF-kappaB were not significantly induced by IL-2 stimulation. Our results showing that GC suppressed IL-5 production by human CD4+ T cells activated by two distinct stimuli, TCR and IL-2R stimulation, underscore the efficacy of GC in the treatment of allergic diseases via suppression of T-cell IL-5 synthesis.
Mori
A
A
Department of Medicine, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Japan.
Kaminuma
O
O
Suko
M
M
Inoue
S
S
Ohmura
T
T
Hoshino
A
A
Asakura
Y
Y
Miyazawa
K
K
Yokota
T
T
Okumura
Y
Y
Ito
K
K
Okudaira
H
H
D000485:Allergens / Q000276:immunology*; D001249:Asthma / Q000276:immunology* / Q000473:pathology; D002999:Clone Cells / Q000276:immunology; D003907:Dexamethasone / Q000494:pharmacology; D004742:Enhancer Elements, Genetic; D004802:Eosinophilia / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology; D015848:Interleukin-5 / Q000096:biosynthesis* / Q000235:genetics; D011239:Prednisolone / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000187:drug effects / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects* / Q000276:immunology; D014157:Transcription Factors / Q000378:metabolism
D000485:Allergens; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D015848:Interleukin-5; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D003907:Dexamethasone; D011239:Prednisolone; D006854:Hydrocortisone