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Nitric oxide sustains IL-1β expression in human dendritic cells enhancing their capacity to induce IL-17-producing T-cells.

Obregon C, Graf L, Chung KF, Cesson V, Nicod LP - PLoS ONE (2015)

Bottom Line: NO changed the pattern of cytokine release by LPS-matured DCs, dependent on the concentration of NO, as well as on the timing of its addition to the cells during maturation.Indeed, DCs treated with NO efficiently induced the release of IL-17 by T-cells through IL-1β.Our work highlights the important role that NO may play in sustaining inflammation during an infection through the preferential differentiation of the Th17 lineage.

View Article: PubMed Central - PubMed

Affiliation: Pneumology Service, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.

ABSTRACT
The role played by lung dendritic cells (DCs) which are influenced by external antigens and by their redox state in controlling inflammation is unclear. We studied the role played by nitric oxide (NO) in DC maturation and function. Human DCs were stimulated with a long-acting NO donor, DPTA NONOate, prior to exposure to lipopolysaccharide (LPS). Dose-and time-dependent experiments were performed with DCs with the aim of measuring the release and gene expression of inflammatory cytokines capable of modifying T-cell differentiation, towardsTh1, Th2 and Th17 cells. NO changed the pattern of cytokine release by LPS-matured DCs, dependent on the concentration of NO, as well as on the timing of its addition to the cells during maturation. Addition of NO before LPS-induced maturation strongly inhibited the release of IL-12, while increasing the expression and release of IL-23, IL-1β and IL-6, which are all involved in Th17 polarization. Indeed, DCs treated with NO efficiently induced the release of IL-17 by T-cells through IL-1β. Our work highlights the important role that NO may play in sustaining inflammation during an infection through the preferential differentiation of the Th17 lineage.

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NO. fails to modify the alloantigen T-cell response but enhances the release of IL-17 during a MLR.DCs were simulated in time-dependent experiments with DPTA NONOATE. 0.6mM and LPS 100ng/ml. 1×105 responder T-cells used for allogenic MLR assays were added to washed DCs for 6 days. A-E, Bioplex of IL-17, IFN-γ, TNF-α, IL-6, IL-13 in 6-day culture at a DC:T-cell ratio of 1:10. Data are expressed as means ±SEM of 7 independent experiments for IL-17 and 6 independent experiments for IFN-γ, TNF-α, IL-6, IL-13. F, T-cell proliferation was measured by incorporation of thymidine at DC:T-cell ratios of 1:10, 1:50 and 1:100. Data are expressed as means ±SEM from 3 independent experiments done in triplicate. *P < 0.05.
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pone.0120134.g003: NO. fails to modify the alloantigen T-cell response but enhances the release of IL-17 during a MLR.DCs were simulated in time-dependent experiments with DPTA NONOATE. 0.6mM and LPS 100ng/ml. 1×105 responder T-cells used for allogenic MLR assays were added to washed DCs for 6 days. A-E, Bioplex of IL-17, IFN-γ, TNF-α, IL-6, IL-13 in 6-day culture at a DC:T-cell ratio of 1:10. Data are expressed as means ±SEM of 7 independent experiments for IL-17 and 6 independent experiments for IFN-γ, TNF-α, IL-6, IL-13. F, T-cell proliferation was measured by incorporation of thymidine at DC:T-cell ratios of 1:10, 1:50 and 1:100. Data are expressed as means ±SEM from 3 independent experiments done in triplicate. *P < 0.05.

Mentions: Under the co-stimulatory conditions, DPTA NONOate did not change the proportion of T-cell proliferation measured by incorporation of thymidine, whether it was added 1 or 5 hours before LPS stimulation (Fig. 3F). Interestingly, during the allo-presentation, the NO.-LPS-treated DCs, compared with LPS-treated DCs, were able to increase the release of IL-17 and IL-6 (Fig. 3A and D), while maintaining a strong Th1 response through the release of TNF-α with (enhanced) IFN-γ (Fig. 3B and C). Th2 responses measured by the release of IL-13 were not modulated by DCs pre-treated with NO-LPS (Fig. 3E). These results suggest that NO. has an important ability to modulate DC phenotype, resulting in diverse T-helper responses during the maturation of DCs. NO. did not modify the co-stimulatory molecules required for the allo-presentation to lymphocytes, but alters the kinetics of cytokine release necessary to polarize T-helper responses.


Nitric oxide sustains IL-1β expression in human dendritic cells enhancing their capacity to induce IL-17-producing T-cells.

Obregon C, Graf L, Chung KF, Cesson V, Nicod LP - PLoS ONE (2015)

NO. fails to modify the alloantigen T-cell response but enhances the release of IL-17 during a MLR.DCs were simulated in time-dependent experiments with DPTA NONOATE. 0.6mM and LPS 100ng/ml. 1×105 responder T-cells used for allogenic MLR assays were added to washed DCs for 6 days. A-E, Bioplex of IL-17, IFN-γ, TNF-α, IL-6, IL-13 in 6-day culture at a DC:T-cell ratio of 1:10. Data are expressed as means ±SEM of 7 independent experiments for IL-17 and 6 independent experiments for IFN-γ, TNF-α, IL-6, IL-13. F, T-cell proliferation was measured by incorporation of thymidine at DC:T-cell ratios of 1:10, 1:50 and 1:100. Data are expressed as means ±SEM from 3 independent experiments done in triplicate. *P < 0.05.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4390375&req=5

pone.0120134.g003: NO. fails to modify the alloantigen T-cell response but enhances the release of IL-17 during a MLR.DCs were simulated in time-dependent experiments with DPTA NONOATE. 0.6mM and LPS 100ng/ml. 1×105 responder T-cells used for allogenic MLR assays were added to washed DCs for 6 days. A-E, Bioplex of IL-17, IFN-γ, TNF-α, IL-6, IL-13 in 6-day culture at a DC:T-cell ratio of 1:10. Data are expressed as means ±SEM of 7 independent experiments for IL-17 and 6 independent experiments for IFN-γ, TNF-α, IL-6, IL-13. F, T-cell proliferation was measured by incorporation of thymidine at DC:T-cell ratios of 1:10, 1:50 and 1:100. Data are expressed as means ±SEM from 3 independent experiments done in triplicate. *P < 0.05.
Mentions: Under the co-stimulatory conditions, DPTA NONOate did not change the proportion of T-cell proliferation measured by incorporation of thymidine, whether it was added 1 or 5 hours before LPS stimulation (Fig. 3F). Interestingly, during the allo-presentation, the NO.-LPS-treated DCs, compared with LPS-treated DCs, were able to increase the release of IL-17 and IL-6 (Fig. 3A and D), while maintaining a strong Th1 response through the release of TNF-α with (enhanced) IFN-γ (Fig. 3B and C). Th2 responses measured by the release of IL-13 were not modulated by DCs pre-treated with NO-LPS (Fig. 3E). These results suggest that NO. has an important ability to modulate DC phenotype, resulting in diverse T-helper responses during the maturation of DCs. NO. did not modify the co-stimulatory molecules required for the allo-presentation to lymphocytes, but alters the kinetics of cytokine release necessary to polarize T-helper responses.

Bottom Line: NO changed the pattern of cytokine release by LPS-matured DCs, dependent on the concentration of NO, as well as on the timing of its addition to the cells during maturation.Indeed, DCs treated with NO efficiently induced the release of IL-17 by T-cells through IL-1β.Our work highlights the important role that NO may play in sustaining inflammation during an infection through the preferential differentiation of the Th17 lineage.

View Article: PubMed Central - PubMed

Affiliation: Pneumology Service, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.

ABSTRACT
The role played by lung dendritic cells (DCs) which are influenced by external antigens and by their redox state in controlling inflammation is unclear. We studied the role played by nitric oxide (NO) in DC maturation and function. Human DCs were stimulated with a long-acting NO donor, DPTA NONOate, prior to exposure to lipopolysaccharide (LPS). Dose-and time-dependent experiments were performed with DCs with the aim of measuring the release and gene expression of inflammatory cytokines capable of modifying T-cell differentiation, towardsTh1, Th2 and Th17 cells. NO changed the pattern of cytokine release by LPS-matured DCs, dependent on the concentration of NO, as well as on the timing of its addition to the cells during maturation. Addition of NO before LPS-induced maturation strongly inhibited the release of IL-12, while increasing the expression and release of IL-23, IL-1β and IL-6, which are all involved in Th17 polarization. Indeed, DCs treated with NO efficiently induced the release of IL-17 by T-cells through IL-1β. Our work highlights the important role that NO may play in sustaining inflammation during an infection through the preferential differentiation of the Th17 lineage.

Show MeSH
Related in: MedlinePlus