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5-hydroxytryptamine modulates migration, cytokine and chemokine release and T-cell priming capacity of dendritic cells in vitro and in vivo.

Müller T, Dürk T, Blumenthal B, Grimm M, Cicko S, Panther E, Sorichter S, Herouy Y, Di Virgilio F, Ferrari D, Norgauer J, Idzko M - PLoS ONE (2009)

Bottom Line: Additionally, 5-HT influenced chemokine release by human monocyte-derived DCs: production of the potent Th1 chemoattractant IP-10/CXCL10 was inhibited in mature DCs, whereas CCL22/MDC secretion was up-regulated in both immature and mature DCs.Furthermore, DCs matured in the presence of 5-HT switched to a high IL-10 and low IL-12p70 secreting phenotype.Consistently, 5-HT favoured the outcome of a Th2 immune response both in vitro and in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Pneumology, University Hospital Freiburg, Freiburg, Germany.

ABSTRACT
Beside its well described role in the central and peripheral nervous system 5-hydroxytryptamine (5-HT), commonly known as serotonin, is also a potent immuno-modulator. Serotoninergic receptors (5-HTR) are expressed by a broad range of inflammatory cell types, including dendritic cells (DCs). In this study, we aimed to further characterize the immuno-biological properties of serotoninergic receptors on human monocyte-derived DCs. 5-HT was able to induce oriented migration in immature but not in LPS-matured DCs via activation of 5-HTR(1) and 5-HTR(2) receptor subtypes. Accordingly, 5-HT also increased migration of pulmonary DCs to draining lymph nodes in vivo. By binding to 5-HTR(3), 5-HTR(4) and 5-HTR(7) receptors, 5-HT up-regulated production of the pro-inflammatory cytokine IL-6. Additionally, 5-HT influenced chemokine release by human monocyte-derived DCs: production of the potent Th1 chemoattractant IP-10/CXCL10 was inhibited in mature DCs, whereas CCL22/MDC secretion was up-regulated in both immature and mature DCs. Furthermore, DCs matured in the presence of 5-HT switched to a high IL-10 and low IL-12p70 secreting phenotype. Consistently, 5-HT favoured the outcome of a Th2 immune response both in vitro and in vivo. In summary, our study shows that 5-HT is a potent regulator of human dendritic cell function, and that targeting serotoninergic receptors might be a promising approach for the treatment of inflammatory disorders.

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5-HT modulates T-cell priming capacity of human monocyte-derived DCs.Immature DCs were left untreated or stimulated with 5-HT, or were induced to undergo maturation with LPS in the absence or the presence of indicated concentration of 5-HT for 24 h. DCs were then used to prime purified allogeneic CD4+CD45RA+ naive T cells. After 5 days, supernatants from T cells were evaluated for the secretion of IL-5 (A), IL-13 (B) and IFN-γ (C). Results are expressed as mean pg/ml±SD (n = 3). *p<0.05 between cytokines secreted by T cells stimulated with DC treated or not with 5-HT. (D) Naive mice received 10×106 DO11.10 CD4+ T-cells intravenously on day-2. On day 0 mice were instilled intratracheally with 106 OVA-pulsed, OVA-pulsed 5-HT treated DCs, or unpulsed DCs. On day4 mediastinal lymph node cells were collected and cultured for 4 days. Four days later, supernatants were harvested and analyzed for the presence of IL-4, IL-5, IL-13, and IFN-γ using commercially available ELISAs .
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pone-0006453-g006: 5-HT modulates T-cell priming capacity of human monocyte-derived DCs.Immature DCs were left untreated or stimulated with 5-HT, or were induced to undergo maturation with LPS in the absence or the presence of indicated concentration of 5-HT for 24 h. DCs were then used to prime purified allogeneic CD4+CD45RA+ naive T cells. After 5 days, supernatants from T cells were evaluated for the secretion of IL-5 (A), IL-13 (B) and IFN-γ (C). Results are expressed as mean pg/ml±SD (n = 3). *p<0.05 between cytokines secreted by T cells stimulated with DC treated or not with 5-HT. (D) Naive mice received 10×106 DO11.10 CD4+ T-cells intravenously on day-2. On day 0 mice were instilled intratracheally with 106 OVA-pulsed, OVA-pulsed 5-HT treated DCs, or unpulsed DCs. On day4 mediastinal lymph node cells were collected and cultured for 4 days. Four days later, supernatants were harvested and analyzed for the presence of IL-4, IL-5, IL-13, and IFN-γ using commercially available ELISAs .

Mentions: Starting from our observation that activation of 5-HTR4 and 5-HTR7 subtypes inhibited the production of IL-12p70, which is an important factor influencing the differentiation of Th1 cells, we next analyzed the quality of primary T cell response induced by DC matured in the presence of different concentration of 5-HT. Naive CD4+CD45RA+ allogeneic T cells primed with mDC exposed to various concentration of 5-HT during maturation displayed an impaired Th1 and enhanced Th2 polarization, as determined by the increased production of IL-13 and IL-5 as well as down regulation of IFN-γ (Fig. 6). T cells stimulated with 5-HT pre-treated iDC showed an also higher IL-5 and IL-13 secretion (Fig. 6A/B).


5-hydroxytryptamine modulates migration, cytokine and chemokine release and T-cell priming capacity of dendritic cells in vitro and in vivo.

Müller T, Dürk T, Blumenthal B, Grimm M, Cicko S, Panther E, Sorichter S, Herouy Y, Di Virgilio F, Ferrari D, Norgauer J, Idzko M - PLoS ONE (2009)

5-HT modulates T-cell priming capacity of human monocyte-derived DCs.Immature DCs were left untreated or stimulated with 5-HT, or were induced to undergo maturation with LPS in the absence or the presence of indicated concentration of 5-HT for 24 h. DCs were then used to prime purified allogeneic CD4+CD45RA+ naive T cells. After 5 days, supernatants from T cells were evaluated for the secretion of IL-5 (A), IL-13 (B) and IFN-γ (C). Results are expressed as mean pg/ml±SD (n = 3). *p<0.05 between cytokines secreted by T cells stimulated with DC treated or not with 5-HT. (D) Naive mice received 10×106 DO11.10 CD4+ T-cells intravenously on day-2. On day 0 mice were instilled intratracheally with 106 OVA-pulsed, OVA-pulsed 5-HT treated DCs, or unpulsed DCs. On day4 mediastinal lymph node cells were collected and cultured for 4 days. Four days later, supernatants were harvested and analyzed for the presence of IL-4, IL-5, IL-13, and IFN-γ using commercially available ELISAs .
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2714071&req=5

pone-0006453-g006: 5-HT modulates T-cell priming capacity of human monocyte-derived DCs.Immature DCs were left untreated or stimulated with 5-HT, or were induced to undergo maturation with LPS in the absence or the presence of indicated concentration of 5-HT for 24 h. DCs were then used to prime purified allogeneic CD4+CD45RA+ naive T cells. After 5 days, supernatants from T cells were evaluated for the secretion of IL-5 (A), IL-13 (B) and IFN-γ (C). Results are expressed as mean pg/ml±SD (n = 3). *p<0.05 between cytokines secreted by T cells stimulated with DC treated or not with 5-HT. (D) Naive mice received 10×106 DO11.10 CD4+ T-cells intravenously on day-2. On day 0 mice were instilled intratracheally with 106 OVA-pulsed, OVA-pulsed 5-HT treated DCs, or unpulsed DCs. On day4 mediastinal lymph node cells were collected and cultured for 4 days. Four days later, supernatants were harvested and analyzed for the presence of IL-4, IL-5, IL-13, and IFN-γ using commercially available ELISAs .
Mentions: Starting from our observation that activation of 5-HTR4 and 5-HTR7 subtypes inhibited the production of IL-12p70, which is an important factor influencing the differentiation of Th1 cells, we next analyzed the quality of primary T cell response induced by DC matured in the presence of different concentration of 5-HT. Naive CD4+CD45RA+ allogeneic T cells primed with mDC exposed to various concentration of 5-HT during maturation displayed an impaired Th1 and enhanced Th2 polarization, as determined by the increased production of IL-13 and IL-5 as well as down regulation of IFN-γ (Fig. 6). T cells stimulated with 5-HT pre-treated iDC showed an also higher IL-5 and IL-13 secretion (Fig. 6A/B).

Bottom Line: Additionally, 5-HT influenced chemokine release by human monocyte-derived DCs: production of the potent Th1 chemoattractant IP-10/CXCL10 was inhibited in mature DCs, whereas CCL22/MDC secretion was up-regulated in both immature and mature DCs.Furthermore, DCs matured in the presence of 5-HT switched to a high IL-10 and low IL-12p70 secreting phenotype.Consistently, 5-HT favoured the outcome of a Th2 immune response both in vitro and in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Pneumology, University Hospital Freiburg, Freiburg, Germany.

ABSTRACT
Beside its well described role in the central and peripheral nervous system 5-hydroxytryptamine (5-HT), commonly known as serotonin, is also a potent immuno-modulator. Serotoninergic receptors (5-HTR) are expressed by a broad range of inflammatory cell types, including dendritic cells (DCs). In this study, we aimed to further characterize the immuno-biological properties of serotoninergic receptors on human monocyte-derived DCs. 5-HT was able to induce oriented migration in immature but not in LPS-matured DCs via activation of 5-HTR(1) and 5-HTR(2) receptor subtypes. Accordingly, 5-HT also increased migration of pulmonary DCs to draining lymph nodes in vivo. By binding to 5-HTR(3), 5-HTR(4) and 5-HTR(7) receptors, 5-HT up-regulated production of the pro-inflammatory cytokine IL-6. Additionally, 5-HT influenced chemokine release by human monocyte-derived DCs: production of the potent Th1 chemoattractant IP-10/CXCL10 was inhibited in mature DCs, whereas CCL22/MDC secretion was up-regulated in both immature and mature DCs. Furthermore, DCs matured in the presence of 5-HT switched to a high IL-10 and low IL-12p70 secreting phenotype. Consistently, 5-HT favoured the outcome of a Th2 immune response both in vitro and in vivo. In summary, our study shows that 5-HT is a potent regulator of human dendritic cell function, and that targeting serotoninergic receptors might be a promising approach for the treatment of inflammatory disorders.

Show MeSH
Related in: MedlinePlus