2 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 suc h as chronic asthma and atopic dermatitis. The development of chronic eosinophilic inflammation is dependent on interleukin-5 (IL-5), a sele ctive eosinophil-activating factor, produced by helper T cells, To del ineate the regulatory mechanisms of human IL-5 synthesis, we establish ed allergen-specific CD4(+) T-cell clones from asthmatic patients, GC efficiently suppressed IL-5 synthesis of T-cell clones activated via e ither 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 dexamet hasone. Human IL-5 promoter/enhancer-luciferase gene construct transfe cted to T-cell clones was transcribed on either TCR or IL-2R stimulati on and was clearly downregulated by dexamethasone, indicating that the approximately 500-bp human IL-5 gene segment located 5' upstream of t he coding region contains activation-inducible enhancer elements respo nsible for the regulation by GC. Electrophoretic mobility shift assay analysis suggested that AP-1 and NF-kappa B are among the possible tar gets of GC actions on TCR-stimulated T cells, NF-AT and NF-kappa B wer e not significantly induced by IL-2 stimulation. Our results showing t hat GC suppressed IL-5 production by human CD4(+) T cells activated by two distinct stimuli, TCR and IL-2R stimulation, underscore the effic acy of GC in the treatment of allergic diseases via suppression of T-c ell IL-5 synthesis. (C) 1997 by The American Society of Hematology.