Induction of dendritic cell maturation and modulation of dendritic cell-induced immune responses by prostaglandins

Dendritic cells (DC) are the most potent antigen-presenting cells of the immune system. In this study we investigated the effects of various prostaglandins (PG) on the stimulatory capacity of DC. DC were generated from peripheral progenitor cells in the presence of IL-4 and GM-CSF and stimulated with IL-1, IL-6 and TNF-alpha on day 7. Simultaneously, PG (PGD(2), PGE(1), PGE(2), PGF(2 alpha), PGI(2)) were added at various concentrations (10(-5) to 10(-9) M) on day 7. In all experiments, PGE(2) had the most potent influence on the maturation of the DC, followed by other PG in the order PGE(1) > PGD(2) > PGF(2 alpha) > PGI(2). In addition, the expression of the surface molecules CD40, CD54, CD58, CD80, CD83, CD86 and the MHC class II molecules was upregulated after stimulation with PG. Analysis of DC supernatants after treatment with PG demonstrated significantly higher amounts of the proinflammatory cytokines IL-1 beta, IL-6, TNF-alpha, and IL-12. Addition of PG to DC induced a markedly enhanced proliferation of both naive and activated CD4(+) and CD8(+) T cells in alloantigen-induced MLR assays. Assessment of coculture supernatants after restimulation revealed significantly higher amounts of the Th1-cytokines IL-2 and IFN-gamma and only minimal amounts of IL-4 compared to control cells. No production of IL-10 was observed. The effects of PG on the maturation of DC and enhanced T-cell proliferation could be mimicked by db-cAMP and forskolin, indicating that they were due to elevated cAMP levels. Collectively, our data show that members of the PG family promote the differentiation of DC and enhance their capacity to induce a Th1 immune response.