Interleukin-6 secretion by astrocytes is dynamically regulated by PI3K-mTOR-calcium signaling.
After contusion spinal cord injury (SCI), astrocytes become reactive and form a glial scar. While this reduces spreading of the damage by containing the area of injury, it inhibits regeneration. One strategy to improve the recovery after SCI is therefore to reduce the inhibitory effect of the scar,...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3965459?pdf=render |
| _version_ | 1828484478256807936 |
|---|---|
| author | Simone Codeluppi Teresa Fernandez-Zafra Katalin Sandor Jacob Kjell Qingsong Liu Mathew Abrams Lars Olson Nathanael S Gray Camilla I Svensson Per Uhlén |
| author_facet | Simone Codeluppi Teresa Fernandez-Zafra Katalin Sandor Jacob Kjell Qingsong Liu Mathew Abrams Lars Olson Nathanael S Gray Camilla I Svensson Per Uhlén |
| author_sort | Simone Codeluppi |
| collection | DOAJ |
| description | After contusion spinal cord injury (SCI), astrocytes become reactive and form a glial scar. While this reduces spreading of the damage by containing the area of injury, it inhibits regeneration. One strategy to improve the recovery after SCI is therefore to reduce the inhibitory effect of the scar, once the acute phase of the injury has passed. The pleiotropic cytokine interleukin-6 (IL-6) is secreted immediately after injury and regulates scar formation; however, little is known about the role of IL-6 in the sub-acute phases of SCI. Interestingly, IL-6 also promotes axon regeneration, and therefore its induction in reactive astrocytes may improve regeneration after SCI. We found that IL-6 is expressed by astrocytes and neurons one week post-injury and then declines. Using primary cultures of rat astrocytes we delineated the molecular mechanisms that regulate IL-6 expression and secretion. IL-6 expression requires activation of p38 and depends on NF-κB transcriptional activity. Activation of these pathways in astrocytes occurs when the PI3K-mTOR-AKT pathway is inhibited. Furthermore, we found that an increase in cytosolic calcium concentration was necessary for IL-6 secretion. To induce IL-6 secretion in astrocytes, we used torin2 and rapamycin to block the PI3K-mTOR pathway and increase cytosolic calcium, respectively. Treating injured animals with torin2 and rapamycin for two weeks, starting two weeks after injury when the scar has been formed, lead to a modest effect on mechanical hypersensitivity, limited to the period of treatment. These data, taken together, suggest that treatment with torin2 and rapamycin induces IL-6 secretion by astrocytes and may contribute to the reduction of mechanical hypersensitivity after SCI. |
| first_indexed | 2024-12-11T08:56:30Z |
| format | Article |
| id | doaj.art-d1624774006348739ffd3553c29ebada |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T08:56:30Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-d1624774006348739ffd3553c29ebada2022-12-22T01:13:52ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0193e9264910.1371/journal.pone.0092649Interleukin-6 secretion by astrocytes is dynamically regulated by PI3K-mTOR-calcium signaling.Simone CodeluppiTeresa Fernandez-ZafraKatalin SandorJacob KjellQingsong LiuMathew AbramsLars OlsonNathanael S GrayCamilla I SvenssonPer UhlénAfter contusion spinal cord injury (SCI), astrocytes become reactive and form a glial scar. While this reduces spreading of the damage by containing the area of injury, it inhibits regeneration. One strategy to improve the recovery after SCI is therefore to reduce the inhibitory effect of the scar, once the acute phase of the injury has passed. The pleiotropic cytokine interleukin-6 (IL-6) is secreted immediately after injury and regulates scar formation; however, little is known about the role of IL-6 in the sub-acute phases of SCI. Interestingly, IL-6 also promotes axon regeneration, and therefore its induction in reactive astrocytes may improve regeneration after SCI. We found that IL-6 is expressed by astrocytes and neurons one week post-injury and then declines. Using primary cultures of rat astrocytes we delineated the molecular mechanisms that regulate IL-6 expression and secretion. IL-6 expression requires activation of p38 and depends on NF-κB transcriptional activity. Activation of these pathways in astrocytes occurs when the PI3K-mTOR-AKT pathway is inhibited. Furthermore, we found that an increase in cytosolic calcium concentration was necessary for IL-6 secretion. To induce IL-6 secretion in astrocytes, we used torin2 and rapamycin to block the PI3K-mTOR pathway and increase cytosolic calcium, respectively. Treating injured animals with torin2 and rapamycin for two weeks, starting two weeks after injury when the scar has been formed, lead to a modest effect on mechanical hypersensitivity, limited to the period of treatment. These data, taken together, suggest that treatment with torin2 and rapamycin induces IL-6 secretion by astrocytes and may contribute to the reduction of mechanical hypersensitivity after SCI.http://europepmc.org/articles/PMC3965459?pdf=render |
| spellingShingle | Simone Codeluppi Teresa Fernandez-Zafra Katalin Sandor Jacob Kjell Qingsong Liu Mathew Abrams Lars Olson Nathanael S Gray Camilla I Svensson Per Uhlén Interleukin-6 secretion by astrocytes is dynamically regulated by PI3K-mTOR-calcium signaling. PLoS ONE |
| title | Interleukin-6 secretion by astrocytes is dynamically regulated by PI3K-mTOR-calcium signaling. |
| title_full | Interleukin-6 secretion by astrocytes is dynamically regulated by PI3K-mTOR-calcium signaling. |
| title_fullStr | Interleukin-6 secretion by astrocytes is dynamically regulated by PI3K-mTOR-calcium signaling. |
| title_full_unstemmed | Interleukin-6 secretion by astrocytes is dynamically regulated by PI3K-mTOR-calcium signaling. |
| title_short | Interleukin-6 secretion by astrocytes is dynamically regulated by PI3K-mTOR-calcium signaling. |
| title_sort | interleukin 6 secretion by astrocytes is dynamically regulated by pi3k mtor calcium signaling |
| url | http://europepmc.org/articles/PMC3965459?pdf=render |
| work_keys_str_mv | AT simonecodeluppi interleukin6secretionbyastrocytesisdynamicallyregulatedbypi3kmtorcalciumsignaling AT teresafernandezzafra interleukin6secretionbyastrocytesisdynamicallyregulatedbypi3kmtorcalciumsignaling AT katalinsandor interleukin6secretionbyastrocytesisdynamicallyregulatedbypi3kmtorcalciumsignaling AT jacobkjell interleukin6secretionbyastrocytesisdynamicallyregulatedbypi3kmtorcalciumsignaling AT qingsongliu interleukin6secretionbyastrocytesisdynamicallyregulatedbypi3kmtorcalciumsignaling AT mathewabrams interleukin6secretionbyastrocytesisdynamicallyregulatedbypi3kmtorcalciumsignaling AT larsolson interleukin6secretionbyastrocytesisdynamicallyregulatedbypi3kmtorcalciumsignaling AT nathanaelsgray interleukin6secretionbyastrocytesisdynamicallyregulatedbypi3kmtorcalciumsignaling AT camillaisvensson interleukin6secretionbyastrocytesisdynamicallyregulatedbypi3kmtorcalciumsignaling AT peruhlen interleukin6secretionbyastrocytesisdynamicallyregulatedbypi3kmtorcalciumsignaling |