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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.

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Regulatory effects of PGE2 on CD83 expression and Ag uptake. (A) Day-5 DCs were incubated with PGE2 (1 μM), TNF-α (1,000  U/ml), LPS (10 ng/ml), or PGE2 plus TNF-α. After 48 h, cells were harvested and CD83 expression was measured by flow cytometry. The isotype control (IgG2b) is also presented (dotted lines). (B) Day-5 DCs were  incubated with PGE2 (1 μM), TNF-α (1,000 U/ml), or PGE2 plus  TNF-α. After 24 h, cells were harvested and incubated with FITC-DX  for 30 min at 37°C (controls at 0°C, dotted lines), washed, and analyzed by  flow cytometry.
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Figure 2: Regulatory effects of PGE2 on CD83 expression and Ag uptake. (A) Day-5 DCs were incubated with PGE2 (1 μM), TNF-α (1,000 U/ml), LPS (10 ng/ml), or PGE2 plus TNF-α. After 48 h, cells were harvested and CD83 expression was measured by flow cytometry. The isotype control (IgG2b) is also presented (dotted lines). (B) Day-5 DCs were incubated with PGE2 (1 μM), TNF-α (1,000 U/ml), or PGE2 plus TNF-α. After 24 h, cells were harvested and incubated with FITC-DX for 30 min at 37°C (controls at 0°C, dotted lines), washed, and analyzed by flow cytometry.

Mentions: The combination of PGE2 and TNF-α turned out to be potent in inducing CD83 expression in DCs (Fig. 2 A). Addition of PGE2 (1 μM) along with TNF-α (1,000 U/ml) induced CD83 expression in 75% of the cells within 24 h (data not shown) and in almost all cells within 48 h (Fig. 2 A). Addition of either substance alone also induced CD83 expression, although to a smaller extent (Fig. 2 A). Moreover, treatment with PGE2 plus TNF-α efficiently upregulated the expression of MHC class I and II molecules, adhesion molecules (CD54, CD58), and costimulatory molecules (CD80, CD86) in DCs (Fig. 3). The expression of CD40 and CD44 was also enhanced. Inspection of these cells by phase contrast microscopy revealed a pronounced dendritic morphology with numerous large veils, a feature of mature DCs (data not shown; reference 10). Conversely, the ability to capture soluble Ag (DX) by mannose receptor–mediated endocytosis was almost completely downregulated in DCs cultured in the presence of PGE2 and TNF-α (Fig. 2 B). Again, either substance alone also downmodulated Ag uptake, although less efficiently.


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)

Regulatory effects of PGE2 on CD83 expression and Ag uptake. (A) Day-5 DCs were incubated with PGE2 (1 μM), TNF-α (1,000  U/ml), LPS (10 ng/ml), or PGE2 plus TNF-α. After 48 h, cells were harvested and CD83 expression was measured by flow cytometry. The isotype control (IgG2b) is also presented (dotted lines). (B) Day-5 DCs were  incubated with PGE2 (1 μM), TNF-α (1,000 U/ml), or PGE2 plus  TNF-α. After 24 h, cells were harvested and incubated with FITC-DX  for 30 min at 37°C (controls at 0°C, dotted lines), washed, and analyzed by  flow cytometry.
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Related In: Results  -  Collection

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Figure 2: Regulatory effects of PGE2 on CD83 expression and Ag uptake. (A) Day-5 DCs were incubated with PGE2 (1 μM), TNF-α (1,000 U/ml), LPS (10 ng/ml), or PGE2 plus TNF-α. After 48 h, cells were harvested and CD83 expression was measured by flow cytometry. The isotype control (IgG2b) is also presented (dotted lines). (B) Day-5 DCs were incubated with PGE2 (1 μM), TNF-α (1,000 U/ml), or PGE2 plus TNF-α. After 24 h, cells were harvested and incubated with FITC-DX for 30 min at 37°C (controls at 0°C, dotted lines), washed, and analyzed by flow cytometry.
Mentions: The combination of PGE2 and TNF-α turned out to be potent in inducing CD83 expression in DCs (Fig. 2 A). Addition of PGE2 (1 μM) along with TNF-α (1,000 U/ml) induced CD83 expression in 75% of the cells within 24 h (data not shown) and in almost all cells within 48 h (Fig. 2 A). Addition of either substance alone also induced CD83 expression, although to a smaller extent (Fig. 2 A). Moreover, treatment with PGE2 plus TNF-α efficiently upregulated the expression of MHC class I and II molecules, adhesion molecules (CD54, CD58), and costimulatory molecules (CD80, CD86) in DCs (Fig. 3). The expression of CD40 and CD44 was also enhanced. Inspection of these cells by phase contrast microscopy revealed a pronounced dendritic morphology with numerous large veils, a feature of mature DCs (data not shown; reference 10). Conversely, the ability to capture soluble Ag (DX) by mannose receptor–mediated endocytosis was almost completely downregulated in DCs cultured in the presence of PGE2 and TNF-α (Fig. 2 B). Again, either substance alone also downmodulated Ag uptake, although less efficiently.

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