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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.

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The antiinflammatory effect of BW245C is dependent on DP1 receptor expression on BM-derived cells. WT BM chimeras and DP1 knockout mice BM chimeras were sensitized and challenged as in Fig. 1. (A) BAL fluid differential counts. (B) Airway obstruction to increasing doses of inhaled metacholine was measured as increase in PenH values (% increase from saline) 24 h after the last antigen exposure. (C) CD4+CD25+ T cells from MLNs of WT or DP1 knockout mice BM chimeras were stained intracellularly for the presence of IL-10. The percentage of Foxp3+ cells in CD4+CD25+ T cells was determined by flow cytometry. Data are shown as mean ± SEM. *, P < 0.05. n = 8 mice per group. conc., concentration.
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fig2: The antiinflammatory effect of BW245C is dependent on DP1 receptor expression on BM-derived cells. WT BM chimeras and DP1 knockout mice BM chimeras were sensitized and challenged as in Fig. 1. (A) BAL fluid differential counts. (B) Airway obstruction to increasing doses of inhaled metacholine was measured as increase in PenH values (% increase from saline) 24 h after the last antigen exposure. (C) CD4+CD25+ T cells from MLNs of WT or DP1 knockout mice BM chimeras were stained intracellularly for the presence of IL-10. The percentage of Foxp3+ cells in CD4+CD25+ T cells was determined by flow cytometry. Data are shown as mean ± SEM. *, P < 0.05. n = 8 mice per group. conc., concentration.

Mentions: To exclude nonspecific effects of BW245C treatment on another prostanoid receptor, we made chimeric mice in which the DP1 receptor is absent on hematopoietic cells by reconstituting lethally irradiated WT C57BL/6 mice with DP1−/− C57BL/6 BM cells or as a control with WT cells. In chimeric DP1−/− mice, there was a remarkable fourfold increase in the degree of eosinophilic airway inflammation compared with WT chimeric mice (Fig. 2 A). Treatment with BW245C had the same antiinflammatory effects in the WT C57BL/6 strain as in BALB/c mice but did not suppress inflammation or BHR in DP1−/− chimeric mice (Fig. 2, A and B). Intracellular cytokine staining on MLN cells showed IL-10 production in CD4+CD25+ cells of WT and DP1−/− BM chimeric mice. IL-10 levels were consistently higher in cells of WT BM chimeric mice treated with BW245C compared with vehicle (Fig. 2 C). Moreover, the percentage of Foxp3+ cells was strongly enhanced in BW245C-treated WT chimeric mice. No increased expression of IL-10 and Foxp3 was observed when DP1−/− chimeric mice were treated with BW245C compared with vehicle (Fig. 2 C).


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)

The antiinflammatory effect of BW245C is dependent on DP1 receptor expression on BM-derived cells. WT BM chimeras and DP1 knockout mice BM chimeras were sensitized and challenged as in Fig. 1. (A) BAL fluid differential counts. (B) Airway obstruction to increasing doses of inhaled metacholine was measured as increase in PenH values (% increase from saline) 24 h after the last antigen exposure. (C) CD4+CD25+ T cells from MLNs of WT or DP1 knockout mice BM chimeras were stained intracellularly for the presence of IL-10. The percentage of Foxp3+ cells in CD4+CD25+ T cells was determined by flow cytometry. Data are shown as mean ± SEM. *, P < 0.05. n = 8 mice per group. conc., concentration.
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Related In: Results  -  Collection

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fig2: The antiinflammatory effect of BW245C is dependent on DP1 receptor expression on BM-derived cells. WT BM chimeras and DP1 knockout mice BM chimeras were sensitized and challenged as in Fig. 1. (A) BAL fluid differential counts. (B) Airway obstruction to increasing doses of inhaled metacholine was measured as increase in PenH values (% increase from saline) 24 h after the last antigen exposure. (C) CD4+CD25+ T cells from MLNs of WT or DP1 knockout mice BM chimeras were stained intracellularly for the presence of IL-10. The percentage of Foxp3+ cells in CD4+CD25+ T cells was determined by flow cytometry. Data are shown as mean ± SEM. *, P < 0.05. n = 8 mice per group. conc., concentration.
Mentions: To exclude nonspecific effects of BW245C treatment on another prostanoid receptor, we made chimeric mice in which the DP1 receptor is absent on hematopoietic cells by reconstituting lethally irradiated WT C57BL/6 mice with DP1−/− C57BL/6 BM cells or as a control with WT cells. In chimeric DP1−/− mice, there was a remarkable fourfold increase in the degree of eosinophilic airway inflammation compared with WT chimeric mice (Fig. 2 A). Treatment with BW245C had the same antiinflammatory effects in the WT C57BL/6 strain as in BALB/c mice but did not suppress inflammation or BHR in DP1−/− chimeric mice (Fig. 2, A and B). Intracellular cytokine staining on MLN cells showed IL-10 production in CD4+CD25+ cells of WT and DP1−/− BM chimeric mice. IL-10 levels were consistently higher in cells of WT BM chimeric mice treated with BW245C compared with vehicle (Fig. 2 C). Moreover, the percentage of Foxp3+ cells was strongly enhanced in BW245C-treated WT chimeric mice. No increased expression of IL-10 and Foxp3 was observed when DP1−/− chimeric mice were treated with BW245C compared with vehicle (Fig. 2 C).

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