Limits...
Prostaglandin E2 and tumor necrosis factor alpha cooperate to activate human dendritic cells: synergistic activation of interleukin 12 production.

Rieser C, Böck G, Klocker H, Bartsch G, Thurnher M - J. Exp. Med. (1997)

Bottom Line: Among other effects, prostaglandin E2 (PGE2) inhibits the production of IL-12 by macrophages activated with lipopolysaccharide (LPS).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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, University of Innsbruck, A-6020 Innsbruck, Austria.

ABSTRACT
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.

Show MeSH

Related in: MedlinePlus

Mimicry of PGE2 effects on IL-12 synthesis and CD83 expression by nonphysiologic modulators of cAMP. Day-5 DCs were incubated with db-cAMP (100 μM) or forskolin (10 μM) either alone or in  combination with TNF-α (1,000 U/ml). After 48 h, supernatants were  analyzed for the presence of IL-12 using a specific ELISA (A) and the cells  were analyzed for CD83 expression by flow cytometry (B). Data are  given as mean ± SEM of four independent experiments.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2199106&req=5

Figure 4: Mimicry of PGE2 effects on IL-12 synthesis and CD83 expression by nonphysiologic modulators of cAMP. Day-5 DCs were incubated with db-cAMP (100 μM) or forskolin (10 μM) either alone or in combination with TNF-α (1,000 U/ml). After 48 h, supernatants were analyzed for the presence of IL-12 using a specific ELISA (A) and the cells were analyzed for CD83 expression by flow cytometry (B). Data are given as mean ± SEM of four independent experiments.

Mentions: Most of the effects of PGE2 are mediated by the intracellular second messenger cAMP (24). Therefore, PGE2 effects can be mimicked by nonphysiologic modulators of cAMP such as forskolin and db-cAMP. To investigate the mechanism of the stimulatory effects of PGE2 on DCs, we tested the effects of forskolin or db-cAMP either alone or in the presence of TNF-α on IL-12 synthesis and CD83 expression in human DCs. Fig. 4 A demonstrates that db-cAMP (100 μM) stimulated low level IL-12 production and synergized with TNF-α to induce substantial IL-12 production by DCs. CD83 expression was also induced by db-cAMP (Fig. 4 B). Forskolin at 10 μM failed to induce IL-12 production (Fig. 4 A). Higher concentrations of forskolin could not be tested due to the high toxicity of this compound. However, in the presence of TNF-α forskolin at 10 μM induced measurable IL-12 production (Fig. 4 A). Forskolin also induced CD83 expression (Fig. 4 B).


Prostaglandin E2 and tumor necrosis factor alpha cooperate to activate human dendritic cells: synergistic activation of interleukin 12 production.

Rieser C, Böck G, Klocker H, Bartsch G, Thurnher M - J. Exp. Med. (1997)

Mimicry of PGE2 effects on IL-12 synthesis and CD83 expression by nonphysiologic modulators of cAMP. Day-5 DCs were incubated with db-cAMP (100 μM) or forskolin (10 μM) either alone or in  combination with TNF-α (1,000 U/ml). After 48 h, supernatants were  analyzed for the presence of IL-12 using a specific ELISA (A) and the cells  were analyzed for CD83 expression by flow cytometry (B). Data are  given as mean ± SEM of four independent experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199106&req=5

Figure 4: Mimicry of PGE2 effects on IL-12 synthesis and CD83 expression by nonphysiologic modulators of cAMP. Day-5 DCs were incubated with db-cAMP (100 μM) or forskolin (10 μM) either alone or in combination with TNF-α (1,000 U/ml). After 48 h, supernatants were analyzed for the presence of IL-12 using a specific ELISA (A) and the cells were analyzed for CD83 expression by flow cytometry (B). Data are given as mean ± SEM of four independent experiments.
Mentions: Most of the effects of PGE2 are mediated by the intracellular second messenger cAMP (24). Therefore, PGE2 effects can be mimicked by nonphysiologic modulators of cAMP such as forskolin and db-cAMP. To investigate the mechanism of the stimulatory effects of PGE2 on DCs, we tested the effects of forskolin or db-cAMP either alone or in the presence of TNF-α on IL-12 synthesis and CD83 expression in human DCs. Fig. 4 A demonstrates that db-cAMP (100 μM) stimulated low level IL-12 production and synergized with TNF-α to induce substantial IL-12 production by DCs. CD83 expression was also induced by db-cAMP (Fig. 4 B). Forskolin at 10 μM failed to induce IL-12 production (Fig. 4 A). Higher concentrations of forskolin could not be tested due to the high toxicity of this compound. However, in the presence of TNF-α forskolin at 10 μM induced measurable IL-12 production (Fig. 4 A). Forskolin also induced CD83 expression (Fig. 4 B).

Bottom Line: Among other effects, prostaglandin E2 (PGE2) inhibits the production of IL-12 by macrophages activated with lipopolysaccharide (LPS).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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, University of Innsbruck, A-6020 Innsbruck, Austria.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus