PROSTAGLANDIN-E2 AND TUMOR-NECROSIS-FACTOR-ALPHA COOPERATE TO ACTIVATE HUMAN DENDRITIC CELLS - SYNERGISTIC ACTIVATION OF INTERLEUKIN-12 PRODUCTION

Interleukin (IL)-12 is a proinflammatory cytokine that contributes to innate resistance and to the development of antigen-specific T cell re sponses. Among other effects, prostaglandin E2 (PGE2) inhibits the pro duction of IL-12. by macrophages activated with lipopolysaccharide (LP S). Here we investigated the effects of PGE2 on human dendritic cells (DCs) which develop in the presence of GM-CSF and IL-4. We demonstrate that in the absence of LPS, PGE2 dose dependently stimulated the prod uction of IL-12 by DCs. Although PGE2 alone stimulated the production of low amounts of IL-12 only, it synergized with tumor necrosis factor (TNF)-alpha to induce high levels of IL-12 production by DCs. Additio n of TNF-alpha in the absence of PGE2 had no effect on IL-12 productio n. Conversely, in the presence of LPS, PGE2 inhibited IL-12 production by DCs in a dose-dependent manner. The combination of PGE2 and TNF-al pha efficiently silenced mannose receptor-mediated endocytosis in DCs and readily induced neo-expression of the CD83 antigen. In addition, t he expression of various surface antigens such as major histocompatibi lity complex class I and II, adhesion, as well as costimulatory molecu les was upregulated by this treatment. The effects of PGE2 on IL-12 sy nthesis and CD83 expression could be mimicked by dibutyryl-cAMP and fo rskolin, indicating that they were due to the intracellular elevation of cAMP levels. DC treated with PGE2 and TNF-alpha were most potent in stimulating allogeneic T cell proliferation. Our data demonstrate tha t PGE2 contributes to the maturation of human DCs and that PGE2 can be a potent enhancer of IL-12 production by human DCs.