Interleukin-6 promotes the production of interleukin-4 and interleukin-5 by interleukin-2-dependent and -independent mechanisms in freshly isolated human T cells

T helper 2 (Th2) cytokines [interleukin (IL)-4 and IL-5] play a central role in the development of allergic immune responses. After allergen provocation, the expression of Th2 cytokines is rapidly up-regulated in atopy and asthma. IL-6 is a multifunctional cytokine that is able to direct Th2 immune responses and is secreted by multiple tissue cell types. This study shows that IL-6 induces up-regulation of IL-4 and IL-5 after short (5 min) preincubation periods in freshly isolated, alpha-CD3/alpha-CD28-stimulated T cells. After longer preincubation periods with IL-6 (12 and 24 hr), the priming effect on IL-4 production gradually disappears, whereas the effect on IL-5 becomes more pronounced. In contrast, a small but significant inhibitory effect is found on the production of the Th1 cytokine interferon-gamma. Additional experiments indicate that the long-term priming effect of IL-6 on IL-5 production is dependent on IL-2 signalling. This is not the case for the short-term IL-6 effect on IL-5 secretion, where the p38 mitogen-activated protein kinase-dependent induction of activator protein-1 DNA-binding activity is involved, independent of signal transducer and activator of transcription 3 phosphorylation. In summary, these data demonstrate that the short-term and long-term priming effects of IL-6 on Th2 cytokine production are regulated by different mechanisms.