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Down-regulating cyclin-dependent kinase 9 of alloreactive CD4(+) T cells prolongs allograft survival

CDK9 (Cyclin-dependent kinase 9)/Cyclin T1/RNA polymerase II pathway has been demonstrated to promote the development of several inflammatory diseases, such as arthritis or atherosclerosis, however, its roles in allotransplantation rejection have not been addressed. Here, we found that CDK9/Cyclin T...

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Autores principales: Zhan, Yang, Han, Yeming, Sun, Hukui, Liang, Ting, Zhang, Chao, Song, Jing, Hou, Guihua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5041884/
https://www.ncbi.nlm.nih.gov/pubmed/27102157
http://dx.doi.org/10.18632/oncotarget.8804
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author Zhan, Yang
Han, Yeming
Sun, Hukui
Liang, Ting
Zhang, Chao
Song, Jing
Hou, Guihua
author_facet Zhan, Yang
Han, Yeming
Sun, Hukui
Liang, Ting
Zhang, Chao
Song, Jing
Hou, Guihua
author_sort Zhan, Yang
collection PubMed
description CDK9 (Cyclin-dependent kinase 9)/Cyclin T1/RNA polymerase II pathway has been demonstrated to promote the development of several inflammatory diseases, such as arthritis or atherosclerosis, however, its roles in allotransplantation rejection have not been addressed. Here, we found that CDK9/Cyclin T1 were apparently up-regulated in the allogeneic group, which was positively correlated with allograft damage. CDK9 was inhibited obviously in naive splenic CD4(+) T cells treated 6 h with 3 μM PHA767491 (a CDK9 inhibitor), and adoptive transfer of these CD4(+) T cells into allografted SCID mice resulted in prolonged survival compared with the group without PHA767491 pretreated. Decelerated rejection was correlated with enhanced IL-4 and IL-10 production and with decreased IFN-γ production by alloreactive T cells. More interestingly, we found that CDK9(42), not CDK9(55), was high expressed in allorejection group, which could be prominently dampened with PHA767491 treatment. The expression of CDK9(42) was consistent with its downstream molecule RNA polymerase II. Altogether, our findings revealed the crucial role of CDK9/Cyclin T1/Pol II pathway in promoting allorejection at multiple levels and may provide a new approach for transplantation tolerance induction through targeting CDK9.
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spelling pubmed-50418842016-10-10 Down-regulating cyclin-dependent kinase 9 of alloreactive CD4(+) T cells prolongs allograft survival Zhan, Yang Han, Yeming Sun, Hukui Liang, Ting Zhang, Chao Song, Jing Hou, Guihua Oncotarget Research Paper: Immunology CDK9 (Cyclin-dependent kinase 9)/Cyclin T1/RNA polymerase II pathway has been demonstrated to promote the development of several inflammatory diseases, such as arthritis or atherosclerosis, however, its roles in allotransplantation rejection have not been addressed. Here, we found that CDK9/Cyclin T1 were apparently up-regulated in the allogeneic group, which was positively correlated with allograft damage. CDK9 was inhibited obviously in naive splenic CD4(+) T cells treated 6 h with 3 μM PHA767491 (a CDK9 inhibitor), and adoptive transfer of these CD4(+) T cells into allografted SCID mice resulted in prolonged survival compared with the group without PHA767491 pretreated. Decelerated rejection was correlated with enhanced IL-4 and IL-10 production and with decreased IFN-γ production by alloreactive T cells. More interestingly, we found that CDK9(42), not CDK9(55), was high expressed in allorejection group, which could be prominently dampened with PHA767491 treatment. The expression of CDK9(42) was consistent with its downstream molecule RNA polymerase II. Altogether, our findings revealed the crucial role of CDK9/Cyclin T1/Pol II pathway in promoting allorejection at multiple levels and may provide a new approach for transplantation tolerance induction through targeting CDK9. Impact Journals LLC 2016-04-18 /pmc/articles/PMC5041884/ /pubmed/27102157 http://dx.doi.org/10.18632/oncotarget.8804 Text en Copyright: © 2016 Zhan et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper: Immunology
Zhan, Yang
Han, Yeming
Sun, Hukui
Liang, Ting
Zhang, Chao
Song, Jing
Hou, Guihua
Down-regulating cyclin-dependent kinase 9 of alloreactive CD4(+) T cells prolongs allograft survival
title Down-regulating cyclin-dependent kinase 9 of alloreactive CD4(+) T cells prolongs allograft survival
title_full Down-regulating cyclin-dependent kinase 9 of alloreactive CD4(+) T cells prolongs allograft survival
title_fullStr Down-regulating cyclin-dependent kinase 9 of alloreactive CD4(+) T cells prolongs allograft survival
title_full_unstemmed Down-regulating cyclin-dependent kinase 9 of alloreactive CD4(+) T cells prolongs allograft survival
title_short Down-regulating cyclin-dependent kinase 9 of alloreactive CD4(+) T cells prolongs allograft survival
title_sort down-regulating cyclin-dependent kinase 9 of alloreactive cd4(+) t cells prolongs allograft survival
topic Research Paper: Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5041884/
https://www.ncbi.nlm.nih.gov/pubmed/27102157
http://dx.doi.org/10.18632/oncotarget.8804
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