Cargando…
The Interplay between Cyclic AMP, MAPK, and NF-κB Pathways in Response to Proinflammatory Signals in Microglia
Cyclic AMP is an important intracellular regulator of microglial cell homeostasis and its negative perturbation through proinflammatory signaling results in microglial cell activation. Though cytokines, TNF-α and IL-1β, decrease intracellular cyclic AMP, the mechanism by which this occurs is poorly...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi Publishing Corporation
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334621/ https://www.ncbi.nlm.nih.gov/pubmed/25722974 http://dx.doi.org/10.1155/2015/308461 |
_version_ | 1782358218446471168 |
---|---|
author | Ghosh, Mousumi Aguirre, Vladimir Wai, Khine Felfly, Hady Dietrich, W. Dalton Pearse, Damien D. |
author_facet | Ghosh, Mousumi Aguirre, Vladimir Wai, Khine Felfly, Hady Dietrich, W. Dalton Pearse, Damien D. |
author_sort | Ghosh, Mousumi |
collection | PubMed |
description | Cyclic AMP is an important intracellular regulator of microglial cell homeostasis and its negative perturbation through proinflammatory signaling results in microglial cell activation. Though cytokines, TNF-α and IL-1β, decrease intracellular cyclic AMP, the mechanism by which this occurs is poorly understood. The current study examined which signaling pathways are responsible for decreasing cyclic AMP in microglia following TNF-α stimulation and sought to identify the role cyclic AMP plays in regulating these pathways. In EOC2 microglia, TNF-α produced a dramatic reduction in cyclic AMP and increased cyclic AMP-dependent PDE activity that could be antagonized by Rolipram, myristoylated-PKI, PD98059, or JSH-23, implicating a role for PDE4, PKA, MEK, and NF-κB in this regulation. Following TNF-α there were significant increases in iNOS and COX-2 immunoreactivity, phosphorylated ERK1/2 and NF-κB-p65, IκB degradation, and NF-κB p65 nuclear translocation, which were reduced in the presence of high levels of cyclic AMP, indicating that reductions in cyclic AMP during cytokine stimulation are important for removing its inhibitory action on NF-κB activation and subsequent proinflammatory gene expression. Further elucidation of the signaling crosstalk involved in decreasing cyclic AMP in response to inflammatory signals may provide novel therapeutic targets for modulating microglial cell activation during neurological injury and disease. |
format | Online Article Text |
id | pubmed-4334621 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Hindawi Publishing Corporation |
record_format | MEDLINE/PubMed |
spelling | pubmed-43346212015-02-26 The Interplay between Cyclic AMP, MAPK, and NF-κB Pathways in Response to Proinflammatory Signals in Microglia Ghosh, Mousumi Aguirre, Vladimir Wai, Khine Felfly, Hady Dietrich, W. Dalton Pearse, Damien D. Biomed Res Int Research Article Cyclic AMP is an important intracellular regulator of microglial cell homeostasis and its negative perturbation through proinflammatory signaling results in microglial cell activation. Though cytokines, TNF-α and IL-1β, decrease intracellular cyclic AMP, the mechanism by which this occurs is poorly understood. The current study examined which signaling pathways are responsible for decreasing cyclic AMP in microglia following TNF-α stimulation and sought to identify the role cyclic AMP plays in regulating these pathways. In EOC2 microglia, TNF-α produced a dramatic reduction in cyclic AMP and increased cyclic AMP-dependent PDE activity that could be antagonized by Rolipram, myristoylated-PKI, PD98059, or JSH-23, implicating a role for PDE4, PKA, MEK, and NF-κB in this regulation. Following TNF-α there were significant increases in iNOS and COX-2 immunoreactivity, phosphorylated ERK1/2 and NF-κB-p65, IκB degradation, and NF-κB p65 nuclear translocation, which were reduced in the presence of high levels of cyclic AMP, indicating that reductions in cyclic AMP during cytokine stimulation are important for removing its inhibitory action on NF-κB activation and subsequent proinflammatory gene expression. Further elucidation of the signaling crosstalk involved in decreasing cyclic AMP in response to inflammatory signals may provide novel therapeutic targets for modulating microglial cell activation during neurological injury and disease. Hindawi Publishing Corporation 2015 2015-02-05 /pmc/articles/PMC4334621/ /pubmed/25722974 http://dx.doi.org/10.1155/2015/308461 Text en Copyright © 2015 Mousumi Ghosh et al. https://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Ghosh, Mousumi Aguirre, Vladimir Wai, Khine Felfly, Hady Dietrich, W. Dalton Pearse, Damien D. The Interplay between Cyclic AMP, MAPK, and NF-κB Pathways in Response to Proinflammatory Signals in Microglia |
title | The Interplay between Cyclic AMP, MAPK, and NF-κB Pathways in Response to Proinflammatory Signals in Microglia |
title_full | The Interplay between Cyclic AMP, MAPK, and NF-κB Pathways in Response to Proinflammatory Signals in Microglia |
title_fullStr | The Interplay between Cyclic AMP, MAPK, and NF-κB Pathways in Response to Proinflammatory Signals in Microglia |
title_full_unstemmed | The Interplay between Cyclic AMP, MAPK, and NF-κB Pathways in Response to Proinflammatory Signals in Microglia |
title_short | The Interplay between Cyclic AMP, MAPK, and NF-κB Pathways in Response to Proinflammatory Signals in Microglia |
title_sort | interplay between cyclic amp, mapk, and nf-κb pathways in response to proinflammatory signals in microglia |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334621/ https://www.ncbi.nlm.nih.gov/pubmed/25722974 http://dx.doi.org/10.1155/2015/308461 |
work_keys_str_mv | AT ghoshmousumi theinterplaybetweencyclicampmapkandnfkbpathwaysinresponsetoproinflammatorysignalsinmicroglia AT aguirrevladimir theinterplaybetweencyclicampmapkandnfkbpathwaysinresponsetoproinflammatorysignalsinmicroglia AT waikhine theinterplaybetweencyclicampmapkandnfkbpathwaysinresponsetoproinflammatorysignalsinmicroglia AT felflyhady theinterplaybetweencyclicampmapkandnfkbpathwaysinresponsetoproinflammatorysignalsinmicroglia AT dietrichwdalton theinterplaybetweencyclicampmapkandnfkbpathwaysinresponsetoproinflammatorysignalsinmicroglia AT pearsedamiend theinterplaybetweencyclicampmapkandnfkbpathwaysinresponsetoproinflammatorysignalsinmicroglia AT ghoshmousumi interplaybetweencyclicampmapkandnfkbpathwaysinresponsetoproinflammatorysignalsinmicroglia AT aguirrevladimir interplaybetweencyclicampmapkandnfkbpathwaysinresponsetoproinflammatorysignalsinmicroglia AT waikhine interplaybetweencyclicampmapkandnfkbpathwaysinresponsetoproinflammatorysignalsinmicroglia AT felflyhady interplaybetweencyclicampmapkandnfkbpathwaysinresponsetoproinflammatorysignalsinmicroglia AT dietrichwdalton interplaybetweencyclicampmapkandnfkbpathwaysinresponsetoproinflammatorysignalsinmicroglia AT pearsedamiend interplaybetweencyclicampmapkandnfkbpathwaysinresponsetoproinflammatorysignalsinmicroglia |