DIFFERENTIAL MODULATION OF T-HELPER TYPE-1 (TH1) AND T-HELPER TYPE-2 (TH2) CYTOKINE SECRETION BY PROSTAGLANDIN E(2) CRITICALLY DEPENDS ON INTERLEUKIN-2

Prostaglandin E(2) (PGE(2)) favors T helper type 2 (Th2)-like cytokine secretion profiles in murine and human CD4(+) T cells by inhibiting the production of the Th1-associated cytokines interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) and up-regulating the production of the Th2-associated cytokines IL-4 and IL-5 in a dose-dependent way. However, the potent inhibition of IL-2 production by PGE(2) seems to be in contrast with the simultaneous up-regulation of IL-4 and IL-5 production, because the induction of these cytokines requires IL-2. We, therefore, investigated to which extent the net modulatory effect of PGE(2) is determined by the availability of IL-2. To this aim, we examined the effects of PGE(2) on the cytokine secretion profiles of a panel of human Th0 clones upon stimulation via different activation pathways, resulting either in high or low IL-2 production. The differential modulation of Th1 and Th2 cytokines by PGE(2) was observed only upon modes of stimulation resulting in high IL-2 production. When IL-2 production was low, PGE(2) inhibited the secretion of all four cytokines. These different modulation patterns were directly related to the IL-2 availability, because (i) neutralizing antibody to IL-2 abrogated the up-regulatory effect of PGE(2) on IL-4 and IL-5 secretion in experiments with high endogenous IL-2 levels, (ii) lack of differential cytokine modulation by PGE(2) in conditions with low levels of endogenous IL-2 could be restored with exogenous IL-2, and (iii) cell viability was comparable in all conditions. These results demonstrate that the net modulatory effect of PGE(2) on the cytokine secretion profile of T cells critically depends on the availability of IL-2. Since this parameter varies with the experimental conditions and the T cell population studied, this finding may explain why certain immune responses may be either up- or down-regulated by PGE(2) under different conditions.