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Selective induction of alternatively spliced FynT isoform by TNF facilitates persistent inflammatory responses in astrocytes

Fyn tyrosine kinase has been implicated in the pathogenesis of Alzheimer’s disease (AD). We have previously reported that upregulation of the FynT isoform in AD brains was partly associated with astrocyte activation. In this study, we demonstrated selective FynT induction in murine cortex and primar...

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Autores principales: Lee, Chingli, Low, Clara Y. B., Wong, Siew Ying, Lai, Mitchell K. P., Tan, Michelle G. K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339870/
https://www.ncbi.nlm.nih.gov/pubmed/28266558
http://dx.doi.org/10.1038/srep43651
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author Lee, Chingli
Low, Clara Y. B.
Wong, Siew Ying
Lai, Mitchell K. P.
Tan, Michelle G. K.
author_facet Lee, Chingli
Low, Clara Y. B.
Wong, Siew Ying
Lai, Mitchell K. P.
Tan, Michelle G. K.
author_sort Lee, Chingli
collection PubMed
description Fyn tyrosine kinase has been implicated in the pathogenesis of Alzheimer’s disease (AD). We have previously reported that upregulation of the FynT isoform in AD brains was partly associated with astrocyte activation. In this study, we demonstrated selective FynT induction in murine cortex and primary astrocyte culture after prolonged exposure to inflammatory stimulants, suggesting that FynT may mediate persistent neuroinflammation. To delineate the functional role of astrocytic FynT in association with TNF-mediated inflammatory responses, immortalized normal human astrocytes (iNHA) stably expressing FynT kinase constitutively active (FynT-CA) or kinase dead (FynT-KD) mutants were treated with TNF and compared for inflammatory responses using high-throughput real-time RT-PCR and Luminex multi-analyte immunoassays. FynT-CA but not FynT-KD mutant exhibited drastic induction of proinflammatory cytokines and chemokines after prolonged exposure to TNF, which could be attenuated by treating with Fyn kinase inhibitor PP2 or silencing via FynT-specific DsiRNA. FynT kinase activity-dependent induction of PKCδ expression, PKCδ phosphorylation, as well as NFκB activation was detected at the late phase but not the early phase of TNF signaling. In conclusion, selective FynT induction by TNF may facilitate persistent inflammatory responses in astrocytes, which is highly relevant to chronic neuroinflammation in neurodegenerative diseases including but not limited to AD.
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spelling pubmed-53398702017-03-10 Selective induction of alternatively spliced FynT isoform by TNF facilitates persistent inflammatory responses in astrocytes Lee, Chingli Low, Clara Y. B. Wong, Siew Ying Lai, Mitchell K. P. Tan, Michelle G. K. Sci Rep Article Fyn tyrosine kinase has been implicated in the pathogenesis of Alzheimer’s disease (AD). We have previously reported that upregulation of the FynT isoform in AD brains was partly associated with astrocyte activation. In this study, we demonstrated selective FynT induction in murine cortex and primary astrocyte culture after prolonged exposure to inflammatory stimulants, suggesting that FynT may mediate persistent neuroinflammation. To delineate the functional role of astrocytic FynT in association with TNF-mediated inflammatory responses, immortalized normal human astrocytes (iNHA) stably expressing FynT kinase constitutively active (FynT-CA) or kinase dead (FynT-KD) mutants were treated with TNF and compared for inflammatory responses using high-throughput real-time RT-PCR and Luminex multi-analyte immunoassays. FynT-CA but not FynT-KD mutant exhibited drastic induction of proinflammatory cytokines and chemokines after prolonged exposure to TNF, which could be attenuated by treating with Fyn kinase inhibitor PP2 or silencing via FynT-specific DsiRNA. FynT kinase activity-dependent induction of PKCδ expression, PKCδ phosphorylation, as well as NFκB activation was detected at the late phase but not the early phase of TNF signaling. In conclusion, selective FynT induction by TNF may facilitate persistent inflammatory responses in astrocytes, which is highly relevant to chronic neuroinflammation in neurodegenerative diseases including but not limited to AD. Nature Publishing Group 2017-03-07 /pmc/articles/PMC5339870/ /pubmed/28266558 http://dx.doi.org/10.1038/srep43651 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Lee, Chingli
Low, Clara Y. B.
Wong, Siew Ying
Lai, Mitchell K. P.
Tan, Michelle G. K.
Selective induction of alternatively spliced FynT isoform by TNF facilitates persistent inflammatory responses in astrocytes
title Selective induction of alternatively spliced FynT isoform by TNF facilitates persistent inflammatory responses in astrocytes
title_full Selective induction of alternatively spliced FynT isoform by TNF facilitates persistent inflammatory responses in astrocytes
title_fullStr Selective induction of alternatively spliced FynT isoform by TNF facilitates persistent inflammatory responses in astrocytes
title_full_unstemmed Selective induction of alternatively spliced FynT isoform by TNF facilitates persistent inflammatory responses in astrocytes
title_short Selective induction of alternatively spliced FynT isoform by TNF facilitates persistent inflammatory responses in astrocytes
title_sort selective induction of alternatively spliced fynt isoform by tnf facilitates persistent inflammatory responses in astrocytes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339870/
https://www.ncbi.nlm.nih.gov/pubmed/28266558
http://dx.doi.org/10.1038/srep43651
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