The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/11/1603/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 9, November 3, 1997 1603-1608

Brief Definitive Reports

Prostaglandin E2 and Tumor Necrosis Factor {alpha} Cooperate to Activate Human Dendritic Cells: Synergistic Activation of Interleukin 12 Production

Claudia Rieser*, Günther Böck{ddagger}, Helmut Klocker*, Georg Bartsch*, and Martin Thurnher*

From the * Department of Urology, and the {ddagger} Institute for General and Experimental Pathology, University of Innsbruck, A-6020 Innsbruck, Austria

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)-{alpha} to induce high levels of IL-12 production by DCs. Addition of TNF-{alpha} 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-{alpha} 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-{alpha} 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.

Address correspondence to Dr. Martin Thurnher, The Department of Urology, Anichstrasse 35, 6020 Innsbruck, Austria. FAX: 43-512-504-4817; E-mail: martin.thurnher{at}uibk.ac.at


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