Extracellular regulated kinase 1/2 signaling is a critical regulator of interleukin-1β-mediated astrocyte tissue inhibitor of metalloproteinase-1 expression.
Astrocytes are essential for proper central nervous system (CNS) function and are intricately involved in neuroinflammation. Despite evidence that immune-activated astrocytes contribute to many CNS pathologies, little is known about the inflammatory pathways controlling gene expression. Our laborato...
Saved in:
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0056891&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850224979952533504 |
|---|---|
| author | Jerel Fields Irma E Cisneros Kathleen Borgmann Anuja Ghorpade |
| author_facet | Jerel Fields Irma E Cisneros Kathleen Borgmann Anuja Ghorpade |
| author_sort | Jerel Fields |
| collection | DOAJ |
| description | Astrocytes are essential for proper central nervous system (CNS) function and are intricately involved in neuroinflammation. Despite evidence that immune-activated astrocytes contribute to many CNS pathologies, little is known about the inflammatory pathways controlling gene expression. Our laboratory identified altered levels of tissue inhibitor of metalloproteinase (TIMP)-1 in brain lysates from human immunodeficiency virus (HIV)-1 infected patients, compared to age-matched controls, and interleukin (IL)-1β as a key regulator of astrocyte TIMP-1. Additionally, CCAAT enhancer binding protein (C/EBP)β levels are elevated in brain specimens from HIV-1 patients and the transcription factor contributes to astrocyte TIMP-1 expression. In this report we sought to identify key signaling pathways necessary for IL-1β-mediated astrocyte TIMP-1 expression and their interaction with C/EBPβ. Primary human astrocytes were cultured and treated with mitogen activated protein kinase-selective small molecule inhibitors, and IL-1β. TIMP-1 and C/EBPβ mRNA and protein expression were evaluated at 12 and 24 h post-treatment, respectively. TIMP-1 promoter-driven luciferase plasmids were used to evaluate TIMP-1 promoter activity in inhibitor-treated astrocytes. These data show that extracellular regulated kinase (ERK) 1/2-selective inhibitors block IL-1β-induced astrocyte TIMP-1 expression, but did not decrease C/EBPβ expression in parallel. The p38 kinase (p38K) inhibitors partially blocked both IL-1β-induced astrocyte TIMP-1 expression and C/EBPβ expression. The ERK1/2-selective inhibitor abrogated IL-1β-mediated increases in TIMP-1 promoter activity. Our data demonstrate that ERK1/2 activation is critical for IL-1β-mediated astrocyte TIMP-1 expression. ERK1/2-selective inhibition may elicit a compensatory response in the form of enhanced IL-1β-mediated astrocyte C/EBPβ expression, or, alternatively, ERK1/2 signaling may function to moderate IL-1β-mediated astrocyte C/EBPβ expression. Furthermore, p38K activation contributes to IL-1β-induced astrocyte TIMP-1 and C/EBPβ expression. These data suggest that ERK1/2 signals downstream of C/EBPβ to facilitate IL-1β-induced astrocyte TIMP-1 expression. Astrocyte ERK1/2 and p38K signaling may serve as therapeutic targets for manipulating CNS TIMP-1 and C/EBPβ levels, respectively. |
| format | Article |
| id | doaj-art-d3d2f98367b34a249a89451c564371b1 |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-d3d2f98367b34a249a89451c564371b12025-08-20T02:05:29ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0182e5689110.1371/journal.pone.0056891Extracellular regulated kinase 1/2 signaling is a critical regulator of interleukin-1β-mediated astrocyte tissue inhibitor of metalloproteinase-1 expression.Jerel FieldsIrma E CisnerosKathleen BorgmannAnuja GhorpadeAstrocytes are essential for proper central nervous system (CNS) function and are intricately involved in neuroinflammation. Despite evidence that immune-activated astrocytes contribute to many CNS pathologies, little is known about the inflammatory pathways controlling gene expression. Our laboratory identified altered levels of tissue inhibitor of metalloproteinase (TIMP)-1 in brain lysates from human immunodeficiency virus (HIV)-1 infected patients, compared to age-matched controls, and interleukin (IL)-1β as a key regulator of astrocyte TIMP-1. Additionally, CCAAT enhancer binding protein (C/EBP)β levels are elevated in brain specimens from HIV-1 patients and the transcription factor contributes to astrocyte TIMP-1 expression. In this report we sought to identify key signaling pathways necessary for IL-1β-mediated astrocyte TIMP-1 expression and their interaction with C/EBPβ. Primary human astrocytes were cultured and treated with mitogen activated protein kinase-selective small molecule inhibitors, and IL-1β. TIMP-1 and C/EBPβ mRNA and protein expression were evaluated at 12 and 24 h post-treatment, respectively. TIMP-1 promoter-driven luciferase plasmids were used to evaluate TIMP-1 promoter activity in inhibitor-treated astrocytes. These data show that extracellular regulated kinase (ERK) 1/2-selective inhibitors block IL-1β-induced astrocyte TIMP-1 expression, but did not decrease C/EBPβ expression in parallel. The p38 kinase (p38K) inhibitors partially blocked both IL-1β-induced astrocyte TIMP-1 expression and C/EBPβ expression. The ERK1/2-selective inhibitor abrogated IL-1β-mediated increases in TIMP-1 promoter activity. Our data demonstrate that ERK1/2 activation is critical for IL-1β-mediated astrocyte TIMP-1 expression. ERK1/2-selective inhibition may elicit a compensatory response in the form of enhanced IL-1β-mediated astrocyte C/EBPβ expression, or, alternatively, ERK1/2 signaling may function to moderate IL-1β-mediated astrocyte C/EBPβ expression. Furthermore, p38K activation contributes to IL-1β-induced astrocyte TIMP-1 and C/EBPβ expression. These data suggest that ERK1/2 signals downstream of C/EBPβ to facilitate IL-1β-induced astrocyte TIMP-1 expression. Astrocyte ERK1/2 and p38K signaling may serve as therapeutic targets for manipulating CNS TIMP-1 and C/EBPβ levels, respectively.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0056891&type=printable |
| spellingShingle | Jerel Fields Irma E Cisneros Kathleen Borgmann Anuja Ghorpade Extracellular regulated kinase 1/2 signaling is a critical regulator of interleukin-1β-mediated astrocyte tissue inhibitor of metalloproteinase-1 expression. PLoS ONE |
| title | Extracellular regulated kinase 1/2 signaling is a critical regulator of interleukin-1β-mediated astrocyte tissue inhibitor of metalloproteinase-1 expression. |
| title_full | Extracellular regulated kinase 1/2 signaling is a critical regulator of interleukin-1β-mediated astrocyte tissue inhibitor of metalloproteinase-1 expression. |
| title_fullStr | Extracellular regulated kinase 1/2 signaling is a critical regulator of interleukin-1β-mediated astrocyte tissue inhibitor of metalloproteinase-1 expression. |
| title_full_unstemmed | Extracellular regulated kinase 1/2 signaling is a critical regulator of interleukin-1β-mediated astrocyte tissue inhibitor of metalloproteinase-1 expression. |
| title_short | Extracellular regulated kinase 1/2 signaling is a critical regulator of interleukin-1β-mediated astrocyte tissue inhibitor of metalloproteinase-1 expression. |
| title_sort | extracellular regulated kinase 1 2 signaling is a critical regulator of interleukin 1β mediated astrocyte tissue inhibitor of metalloproteinase 1 expression |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0056891&type=printable |
| work_keys_str_mv | AT jerelfields extracellularregulatedkinase12signalingisacriticalregulatorofinterleukin1bmediatedastrocytetissueinhibitorofmetalloproteinase1expression AT irmaecisneros extracellularregulatedkinase12signalingisacriticalregulatorofinterleukin1bmediatedastrocytetissueinhibitorofmetalloproteinase1expression AT kathleenborgmann extracellularregulatedkinase12signalingisacriticalregulatorofinterleukin1bmediatedastrocytetissueinhibitorofmetalloproteinase1expression AT anujaghorpade extracellularregulatedkinase12signalingisacriticalregulatorofinterleukin1bmediatedastrocytetissueinhibitorofmetalloproteinase1expression |