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J. Exp. Med.,
Volume 186, Number 9, November 3, 1997 1603-1608
Cooperate to
Activate Human Dendritic Cells: Synergistic Activation of
Interleukin 12 Production
By

From the * Department of Urology, and the Interleukin (IL)-12 is a proinflammatory cytokine that contributes to innate resistance and to
the development of antigen-specific T cell responses. Among other effects, prostaglandin E2
(PGE2) inhibits the production of IL-12 by macrophages activated with lipopolysaccharide
(LPS). 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 production 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)-
Institute for General and Experimental Pathology,
University of Innsbruck, A-6020 Innsbruck, Austria
to induce high levels of IL-12 production by DCs. Addition of TNF-
in the absence of PGE2 had no effect on IL-12 production. Conversely, in the presence of LPS, PGE2
inhibited IL-12 production by DCs in a dose-dependent manner. The combination of PGE2
and TNF-
efficiently silenced mannose receptor-mediated endocytosis in DCs and readily induced neo-expression of the CD83 antigen. In addition, the expression of various surface antigens such as major histocompatibility complex class I and II, adhesion, as well as costimulatory
molecules was upregulated by this treatment. The effects of PGE2 on IL-12 synthesis and
CD83 expression could be mimicked by dibutyryl-cAMP and forskolin, indicating that they were due to the intracellular elevation of cAMP levels. DC treated with PGE2 and TNF-
were most potent in stimulating allogeneic T cell proliferation. Our data demonstrate that
PGE2 contributes to the maturation of human DCs and that PGE2 can be a potent enhancer of
IL-12 production by human DCs.
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