PGE2 is a well known immunomodulator that has multiple effects on the immune system. We demonstrate that PGE2 selectively and dose dependently inhibits IL-2 and IFN-gamma production by mitogenically stimulated human PBL and CD4+ TLC, although at low concentrations IL-4 production is not affected and IL-5 production is even up-regulated. In the tested TLC, PGE2 induced a dramatic elevation (up to 85-fold) of the intracellular cAMP levels. The action of PGE2 may, therefore, be associated with elevation of intracellular cAMP levels, affecting IL-4 and IL-5 differentially from IL-2 and IFN-gamma production. To test this hypothesis we investigated cytokine production by TLC in the absence or presence of agents that affect cAMP levels, either directly (2'-O-dibutyrylcAMP) or through activation of adenylate cyclase (forskolin) or by blocking of phosphodiesterase (3-isobutyl-1-methyl-xanthine). Similar to PGE2, forskolin, 2'-O-dibutyrylcAMP, and 3-isobutyl-1-methyl-xanthine induced inhibition of IL-2 production by TLC and up-regulation of IL-5 production. However, in contrast to PGE2, these agents suppressed IL-4 production although IFN-gamma production was only moderately affected. No significant differences were found between intracellular cAMP levels of mitogenically stimulated Th1 cell clones, which predominantly secrete IL-2 and IFN-gamma, and those of Th2 cell clones, which mainly secrete IL-4 and IL-5. Our results indicate that PGE2 selectively modulates cytokine secretion profiles of human T cells and that elevation of cAMP levels has an important, but possibly not exclusive, regulatory role in this phenomenon.