Limits...
Activation of the D prostanoid 1 receptor suppresses asthma by modulation of lung dendritic cell function and induction of regulatory T cells.

Hammad H, Kool M, Soullié T, Narumiya S, Trottein F, Hoogsteden HC, Lambrecht BN - J. Exp. Med. (2007)

Bottom Line: Prostaglandins (PGs) can enhance or suppress inflammation by acting on different receptors expressed by hematopoietic and nonhematopoietic cells.These effects of DP1 agonist on DCs were mediated by cyclic AMP-dependent protein kinase A.Triggering DP1 on DCs is an important mechanism to induce regulatory T cells and to control the extent of airway inflammation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pulmonary Medicine, Erasmus Medical Center, 3015 GE Rotterdam, Netherlands.

ABSTRACT
Prostaglandins (PGs) can enhance or suppress inflammation by acting on different receptors expressed by hematopoietic and nonhematopoietic cells. Prostaglandin D(2) binds to the D prostanoid (DP)1 and DP2 receptor and is seen as a critical mediator of asthma causing vasodilation, bronchoconstriction, and inflammatory cell influx. Here we show that inhalation of a selective DP1 agonist suppresses the cardinal features of asthma by targeting the function of lung dendritic cells (DCs). In mice treated with DP1 agonist or receiving DP1 agonist-treated DCs, there was an increase in Foxp3(+) CD4(+) regulatory T cells that suppressed inflammation in an interleukin 10-dependent way. These effects of DP1 agonist on DCs were mediated by cyclic AMP-dependent protein kinase A. We furthermore show that activation of DP1 by an endogenous ligand inhibits airway inflammation as chimeric mice with selective hematopoietic loss of DP1 had strongly enhanced airway inflammation and antigen-pulsed DCs lacking DP1 were better at inducing airway T helper 2 responses in the lung. Triggering DP1 on DCs is an important mechanism to induce regulatory T cells and to control the extent of airway inflammation. This pathway could be exploited to design novel treatments for asthma.

Show MeSH

Related in: MedlinePlus

DP-1 activation affects the phenotype of DCs. Mice were sensitized and challenged and treated with DP agonists as in Fig. 1. (A) Single cell suspension was prepared from the lungs of WT or DP1−/− BM chimeric mice, and CD11c+MHCIIhi lung DCs were analyzed for their expression of CD40, CD86, and MHC II. Data are shown as mean fluorescence intensity ± SEM. *, P < 0.05. MFI, mean fluorescence intensity (B) BMDCs from WT or DP-1 knockout mice were pulsed or not with 100 μg/ml of OVA overnight. DCs were also treated for 30 min with vehicle (Vehicle/OVA-DCs) or BW245C before addition of OVA (BW245C/OVA-DCs). DCs were collected, and the expression of CD40, CD80, CD86, and MHC II was analyzed by flow cytometry. (C) Analysis of intracellular IL-10 staining in CD11c+MHCIIhi DCs of OVA-challenged mice treated or not with BW245C.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2118726&req=5

fig3: DP-1 activation affects the phenotype of DCs. Mice were sensitized and challenged and treated with DP agonists as in Fig. 1. (A) Single cell suspension was prepared from the lungs of WT or DP1−/− BM chimeric mice, and CD11c+MHCIIhi lung DCs were analyzed for their expression of CD40, CD86, and MHC II. Data are shown as mean fluorescence intensity ± SEM. *, P < 0.05. MFI, mean fluorescence intensity (B) BMDCs from WT or DP-1 knockout mice were pulsed or not with 100 μg/ml of OVA overnight. DCs were also treated for 30 min with vehicle (Vehicle/OVA-DCs) or BW245C before addition of OVA (BW245C/OVA-DCs). DCs were collected, and the expression of CD40, CD80, CD86, and MHC II was analyzed by flow cytometry. (C) Analysis of intracellular IL-10 staining in CD11c+MHCIIhi DCs of OVA-challenged mice treated or not with BW245C.

Mentions: As PGD2 and BW245C alter some functions of DCs in vivo (22), and ongoing allergic responses depend on DCs (21), we next studied the treatment effect on DC maturation. In BW245C-treated WT chimeric mice, there was a significantly reduced expression of the maturation marker CD86, CD40, and MHC II on lung DCs of OVA-challenged mice (Fig. 3 A). Interestingly, these effects of BW245C were abolished in DP1−/− chimeric mice, except for CD40 whose expression was still reduced compared with vehicle-treated mice (Fig. 3 B). Intracellular IL-10 levels were clearly detectable in lung-derived DCs from OVA-exposed mice (23), but BW245C treatment did not lead to an increased expression (Fig. 3 D).


Activation of the D prostanoid 1 receptor suppresses asthma by modulation of lung dendritic cell function and induction of regulatory T cells.

Hammad H, Kool M, Soullié T, Narumiya S, Trottein F, Hoogsteden HC, Lambrecht BN - J. Exp. Med. (2007)

DP-1 activation affects the phenotype of DCs. Mice were sensitized and challenged and treated with DP agonists as in Fig. 1. (A) Single cell suspension was prepared from the lungs of WT or DP1−/− BM chimeric mice, and CD11c+MHCIIhi lung DCs were analyzed for their expression of CD40, CD86, and MHC II. Data are shown as mean fluorescence intensity ± SEM. *, P < 0.05. MFI, mean fluorescence intensity (B) BMDCs from WT or DP-1 knockout mice were pulsed or not with 100 μg/ml of OVA overnight. DCs were also treated for 30 min with vehicle (Vehicle/OVA-DCs) or BW245C before addition of OVA (BW245C/OVA-DCs). DCs were collected, and the expression of CD40, CD80, CD86, and MHC II was analyzed by flow cytometry. (C) Analysis of intracellular IL-10 staining in CD11c+MHCIIhi DCs of OVA-challenged mice treated or not with BW245C.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2118726&req=5

fig3: DP-1 activation affects the phenotype of DCs. Mice were sensitized and challenged and treated with DP agonists as in Fig. 1. (A) Single cell suspension was prepared from the lungs of WT or DP1−/− BM chimeric mice, and CD11c+MHCIIhi lung DCs were analyzed for their expression of CD40, CD86, and MHC II. Data are shown as mean fluorescence intensity ± SEM. *, P < 0.05. MFI, mean fluorescence intensity (B) BMDCs from WT or DP-1 knockout mice were pulsed or not with 100 μg/ml of OVA overnight. DCs were also treated for 30 min with vehicle (Vehicle/OVA-DCs) or BW245C before addition of OVA (BW245C/OVA-DCs). DCs were collected, and the expression of CD40, CD80, CD86, and MHC II was analyzed by flow cytometry. (C) Analysis of intracellular IL-10 staining in CD11c+MHCIIhi DCs of OVA-challenged mice treated or not with BW245C.
Mentions: As PGD2 and BW245C alter some functions of DCs in vivo (22), and ongoing allergic responses depend on DCs (21), we next studied the treatment effect on DC maturation. In BW245C-treated WT chimeric mice, there was a significantly reduced expression of the maturation marker CD86, CD40, and MHC II on lung DCs of OVA-challenged mice (Fig. 3 A). Interestingly, these effects of BW245C were abolished in DP1−/− chimeric mice, except for CD40 whose expression was still reduced compared with vehicle-treated mice (Fig. 3 B). Intracellular IL-10 levels were clearly detectable in lung-derived DCs from OVA-exposed mice (23), but BW245C treatment did not lead to an increased expression (Fig. 3 D).

Bottom Line: Prostaglandins (PGs) can enhance or suppress inflammation by acting on different receptors expressed by hematopoietic and nonhematopoietic cells.These effects of DP1 agonist on DCs were mediated by cyclic AMP-dependent protein kinase A.Triggering DP1 on DCs is an important mechanism to induce regulatory T cells and to control the extent of airway inflammation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pulmonary Medicine, Erasmus Medical Center, 3015 GE Rotterdam, Netherlands.

ABSTRACT
Prostaglandins (PGs) can enhance or suppress inflammation by acting on different receptors expressed by hematopoietic and nonhematopoietic cells. Prostaglandin D(2) binds to the D prostanoid (DP)1 and DP2 receptor and is seen as a critical mediator of asthma causing vasodilation, bronchoconstriction, and inflammatory cell influx. Here we show that inhalation of a selective DP1 agonist suppresses the cardinal features of asthma by targeting the function of lung dendritic cells (DCs). In mice treated with DP1 agonist or receiving DP1 agonist-treated DCs, there was an increase in Foxp3(+) CD4(+) regulatory T cells that suppressed inflammation in an interleukin 10-dependent way. These effects of DP1 agonist on DCs were mediated by cyclic AMP-dependent protein kinase A. We furthermore show that activation of DP1 by an endogenous ligand inhibits airway inflammation as chimeric mice with selective hematopoietic loss of DP1 had strongly enhanced airway inflammation and antigen-pulsed DCs lacking DP1 were better at inducing airway T helper 2 responses in the lung. Triggering DP1 on DCs is an important mechanism to induce regulatory T cells and to control the extent of airway inflammation. This pathway could be exploited to design novel treatments for asthma.

Show MeSH
Related in: MedlinePlus