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Dendritic Cells Regulate Treg-Th17 Axis in Obstructive Phase of Bile Duct Injury in Murine Biliary Atresia.

Liu YJ, Li K, Yang L, Tang ST, Wang XX, Cao GQ, Li S, Lei HY, Zhang X - PLoS ONE (2015)

Bottom Line: By depleting the Th17 cells, the BA symptoms (onset of jaundice, acholic stools and retarded growth) were attenuated and the survival rate was improved.The level of IL-6, which has been shown to be abundantly secreted by activated dendritic cells (DCs), was remarkably elevated.In conclusion, the DC-regulated Treg-Th17 axis, probably in conjunction with other effector T cells, aggravates progressive inflammatory injury at the time of ductal obstruction.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

ABSTRACT
Several cell types are considered to be effector cells in bile duct injury in rhesus rotavirus (RRV)-induced experimental biliary atresia (BA). Here, we identified an increased T helper 17 (Th17) cell population in a BA mode. By depleting the Th17 cells, the BA symptoms (onset of jaundice, acholic stools and retarded growth) were attenuated and the survival rate was improved. Furthermore, we found that in mice with BA, the percentage of CD4+CD25highFoxp3+ T regulatory (Treg) cells decreased along with the increased percentage of Th17 cells. However, the absolute numbers of Treg and Th17 cells were both increased in liver of RRV-injected mice compared to saline-injected mice. The proportion of Th17 cells at 7 days post-infection was decreased if Treg cells isolated from normal adult mice, but not Treg cells from the livers of mice with BA, were intraperitoneally transferred on day 5 of life. In vitro experiments also showed that Treg cells from mice with BA had a diminished suppressive effect on Th17 cell generation. To determine the mechanisms, we investigated the production of cytokines in the liver. The level of IL-6, which has been shown to be abundantly secreted by activated dendritic cells (DCs), was remarkably elevated. Importantly, in a Treg/Th17 cell suppression assay, IL-6 was demonstrated to paralyze the Treg cells' suppressive effect on Th17 cells and eventually the unrestrained increase of Th17 cells contributed to bile duct injury. In conclusion, the DC-regulated Treg-Th17 axis, probably in conjunction with other effector T cells, aggravates progressive inflammatory injury at the time of ductal obstruction.

No MeSH data available.


Related in: MedlinePlus

Impact of cytokines on Th17 and Treg cells in BA mice.(A) Cytokine levels in the supernatant of liver cell suspensions of RRV or saline injected mice were determined by ELISA and are reported as the mean ± SEM (n = 15). * P<0.05, ** P<0.01, *** P<0.001. (B) Th17 cells detected in culture medium of CD4+ naïve T cells stimulated with plate-bound anti-CD3 and soluble anti-CD28 mAbs in the presence or absence of the indicated cytokines, followed by re-stimulation with PMA and ionomycin 7 days later. The results are reported as the mean ± SEM (n = 10). * P<0.05, ** P<0.01.
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pone.0136214.g006: Impact of cytokines on Th17 and Treg cells in BA mice.(A) Cytokine levels in the supernatant of liver cell suspensions of RRV or saline injected mice were determined by ELISA and are reported as the mean ± SEM (n = 15). * P<0.05, ** P<0.01, *** P<0.001. (B) Th17 cells detected in culture medium of CD4+ naïve T cells stimulated with plate-bound anti-CD3 and soluble anti-CD28 mAbs in the presence or absence of the indicated cytokines, followed by re-stimulation with PMA and ionomycin 7 days later. The results are reported as the mean ± SEM (n = 10). * P<0.05, ** P<0.01.

Mentions: We detected certain cytokines that are probably related to the Th17-Treg imbalance when examining the livers of BA mice. As shown in Fig 6A, significantly higher levels of IFN-γ, IL-6, IL-10, TGF-β and IL-23 were found in the livers of BA mice compared with controls (P<0.05). To evaluate effects of these cytokines on the generation and differentiation of Th17 and Treg cells, purified naïve T cells were cultured in the presence of one or more cytokine milieus. We noted that only TGF-β increased the Treg cell population. The rest of the cytokine identified above, even when highly expressed, did not increase the percentage of Th17 cells, whereas a combination of IL-6 and TGF-β, or IL-6, TGF-β and IL-23, markedly increased the percentage of Th17 cells (Fig 6B). Despite the fact that TNF and IL-10 levels were significantly increased in the livers of BA mice, these cytokines seemed to be not important for Th17 differentiation. The results suggest that IL-6, the cytokine whose levels were markedly increased in the livers of BA mice, helps to polarize the local microenvironment for the production of Th17 cells, but not Treg cells.


Dendritic Cells Regulate Treg-Th17 Axis in Obstructive Phase of Bile Duct Injury in Murine Biliary Atresia.

Liu YJ, Li K, Yang L, Tang ST, Wang XX, Cao GQ, Li S, Lei HY, Zhang X - PLoS ONE (2015)

Impact of cytokines on Th17 and Treg cells in BA mice.(A) Cytokine levels in the supernatant of liver cell suspensions of RRV or saline injected mice were determined by ELISA and are reported as the mean ± SEM (n = 15). * P<0.05, ** P<0.01, *** P<0.001. (B) Th17 cells detected in culture medium of CD4+ naïve T cells stimulated with plate-bound anti-CD3 and soluble anti-CD28 mAbs in the presence or absence of the indicated cytokines, followed by re-stimulation with PMA and ionomycin 7 days later. The results are reported as the mean ± SEM (n = 10). * P<0.05, ** P<0.01.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4556529&req=5

pone.0136214.g006: Impact of cytokines on Th17 and Treg cells in BA mice.(A) Cytokine levels in the supernatant of liver cell suspensions of RRV or saline injected mice were determined by ELISA and are reported as the mean ± SEM (n = 15). * P<0.05, ** P<0.01, *** P<0.001. (B) Th17 cells detected in culture medium of CD4+ naïve T cells stimulated with plate-bound anti-CD3 and soluble anti-CD28 mAbs in the presence or absence of the indicated cytokines, followed by re-stimulation with PMA and ionomycin 7 days later. The results are reported as the mean ± SEM (n = 10). * P<0.05, ** P<0.01.
Mentions: We detected certain cytokines that are probably related to the Th17-Treg imbalance when examining the livers of BA mice. As shown in Fig 6A, significantly higher levels of IFN-γ, IL-6, IL-10, TGF-β and IL-23 were found in the livers of BA mice compared with controls (P<0.05). To evaluate effects of these cytokines on the generation and differentiation of Th17 and Treg cells, purified naïve T cells were cultured in the presence of one or more cytokine milieus. We noted that only TGF-β increased the Treg cell population. The rest of the cytokine identified above, even when highly expressed, did not increase the percentage of Th17 cells, whereas a combination of IL-6 and TGF-β, or IL-6, TGF-β and IL-23, markedly increased the percentage of Th17 cells (Fig 6B). Despite the fact that TNF and IL-10 levels were significantly increased in the livers of BA mice, these cytokines seemed to be not important for Th17 differentiation. The results suggest that IL-6, the cytokine whose levels were markedly increased in the livers of BA mice, helps to polarize the local microenvironment for the production of Th17 cells, but not Treg cells.

Bottom Line: By depleting the Th17 cells, the BA symptoms (onset of jaundice, acholic stools and retarded growth) were attenuated and the survival rate was improved.The level of IL-6, which has been shown to be abundantly secreted by activated dendritic cells (DCs), was remarkably elevated.In conclusion, the DC-regulated Treg-Th17 axis, probably in conjunction with other effector T cells, aggravates progressive inflammatory injury at the time of ductal obstruction.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

ABSTRACT
Several cell types are considered to be effector cells in bile duct injury in rhesus rotavirus (RRV)-induced experimental biliary atresia (BA). Here, we identified an increased T helper 17 (Th17) cell population in a BA mode. By depleting the Th17 cells, the BA symptoms (onset of jaundice, acholic stools and retarded growth) were attenuated and the survival rate was improved. Furthermore, we found that in mice with BA, the percentage of CD4+CD25highFoxp3+ T regulatory (Treg) cells decreased along with the increased percentage of Th17 cells. However, the absolute numbers of Treg and Th17 cells were both increased in liver of RRV-injected mice compared to saline-injected mice. The proportion of Th17 cells at 7 days post-infection was decreased if Treg cells isolated from normal adult mice, but not Treg cells from the livers of mice with BA, were intraperitoneally transferred on day 5 of life. In vitro experiments also showed that Treg cells from mice with BA had a diminished suppressive effect on Th17 cell generation. To determine the mechanisms, we investigated the production of cytokines in the liver. The level of IL-6, which has been shown to be abundantly secreted by activated dendritic cells (DCs), was remarkably elevated. Importantly, in a Treg/Th17 cell suppression assay, IL-6 was demonstrated to paralyze the Treg cells' suppressive effect on Th17 cells and eventually the unrestrained increase of Th17 cells contributed to bile duct injury. In conclusion, the DC-regulated Treg-Th17 axis, probably in conjunction with other effector T cells, aggravates progressive inflammatory injury at the time of ductal obstruction.

No MeSH data available.


Related in: MedlinePlus