Pharmacological inhibition of Akt and downstream pathways modulates the expression of COX-2 and mPGES-1 in activated microglia
<p>Abstract</p> <p>Background</p> <p>Microglia are considered a major target for modulating neuroinflammatory and neurodegenerative disease processes. Upon activation, microglia secrete inflammatory mediators that contribute to the resolution or to further enhancement o...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2012-01-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://www.jneuroinflammation.com/content/9/1/2 |
| _version_ | 1818037766868434944 |
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| author | de Oliveira Antonio CP Candelario-Jalil Eduardo Langbein Julia Wendeburg Lena Bhatia Harsharan S Schlachetzki Johannes CM Biber Knut Fiebich Bernd L |
| author_facet | de Oliveira Antonio CP Candelario-Jalil Eduardo Langbein Julia Wendeburg Lena Bhatia Harsharan S Schlachetzki Johannes CM Biber Knut Fiebich Bernd L |
| author_sort | de Oliveira Antonio CP |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Microglia are considered a major target for modulating neuroinflammatory and neurodegenerative disease processes. Upon activation, microglia secrete inflammatory mediators that contribute to the resolution or to further enhancement of damage in the central nervous system (CNS). Therefore, it is important to study the intracellular pathways that are involved in the expression of the inflammatory mediators. Particularly, the role of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and glycogen synthase kinase-3 (GSK-3) pathways in activated microglia is unclear. Thus, in the present study we investigated the role of Akt and its downstream pathways, GSK-3 and mTOR, in lipopolysaccharide (LPS)-activated primary rat microglia by pharmacological inhibition of these pathways in regard to the expression of cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1 (mPGES-1) and to the production of prostaglandin (PG) E<sub>2 </sub>and PGD<sub>2</sub>.</p> <p>Findings</p> <p>We show that inhibition of Akt by the Akt inhibitor X enhanced the production of PGE<sub>2 </sub>and PGD<sub>2 </sub>without affecting the expression of COX-2, mPGES-1, mPGES-2 and cytosolic prostaglandin E synthase (cPGES). Moreover, inhibition of GSK-3 reduced the expression of both COX-2 and mPGES-1. In contrast, the mTOR inhibitor rapamycin enhanced both COX-2 and mPGES-1 immunoreactivity and the release of PGE<sub>2 </sub>and PGD<sub>2</sub>. Interestingly, NVP-BEZ235, a dual PI3K/mTOR inhibitor, enhanced COX-2 and reduced mPGES-1 immunoreactivity, albeit PGE<sub>2 </sub>and PGD<sub>2 </sub>levels were enhanced in LPS-stimulated microglia. However, this compound also increased PGE<sub>2 </sub>in non-stimulated microglia.</p> <p>Conclusion</p> <p>Taken together, we demonstrate that blockade of mTOR and/or PI3K/Akt enhances prostanoid production and that PI3K/Akt, GSK-3 and mTOR differently regulate the expression of mPGES-1 and COX-2 in activated primary microglia. Therefore, these pathways are potential targets for the development of novel strategies to modulate neuroinflammation.</p> |
| first_indexed | 2024-12-10T07:32:04Z |
| format | Article |
| id | doaj.art-b6c84376d15441689031a6dac0e491e0 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-10T07:32:04Z |
| publishDate | 2012-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-b6c84376d15441689031a6dac0e491e02022-12-22T01:57:32ZengBMCJournal of Neuroinflammation1742-20942012-01-0191210.1186/1742-2094-9-2Pharmacological inhibition of Akt and downstream pathways modulates the expression of COX-2 and mPGES-1 in activated microgliade Oliveira Antonio CPCandelario-Jalil EduardoLangbein JuliaWendeburg LenaBhatia Harsharan SSchlachetzki Johannes CMBiber KnutFiebich Bernd L<p>Abstract</p> <p>Background</p> <p>Microglia are considered a major target for modulating neuroinflammatory and neurodegenerative disease processes. Upon activation, microglia secrete inflammatory mediators that contribute to the resolution or to further enhancement of damage in the central nervous system (CNS). Therefore, it is important to study the intracellular pathways that are involved in the expression of the inflammatory mediators. Particularly, the role of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and glycogen synthase kinase-3 (GSK-3) pathways in activated microglia is unclear. Thus, in the present study we investigated the role of Akt and its downstream pathways, GSK-3 and mTOR, in lipopolysaccharide (LPS)-activated primary rat microglia by pharmacological inhibition of these pathways in regard to the expression of cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1 (mPGES-1) and to the production of prostaglandin (PG) E<sub>2 </sub>and PGD<sub>2</sub>.</p> <p>Findings</p> <p>We show that inhibition of Akt by the Akt inhibitor X enhanced the production of PGE<sub>2 </sub>and PGD<sub>2 </sub>without affecting the expression of COX-2, mPGES-1, mPGES-2 and cytosolic prostaglandin E synthase (cPGES). Moreover, inhibition of GSK-3 reduced the expression of both COX-2 and mPGES-1. In contrast, the mTOR inhibitor rapamycin enhanced both COX-2 and mPGES-1 immunoreactivity and the release of PGE<sub>2 </sub>and PGD<sub>2</sub>. Interestingly, NVP-BEZ235, a dual PI3K/mTOR inhibitor, enhanced COX-2 and reduced mPGES-1 immunoreactivity, albeit PGE<sub>2 </sub>and PGD<sub>2 </sub>levels were enhanced in LPS-stimulated microglia. However, this compound also increased PGE<sub>2 </sub>in non-stimulated microglia.</p> <p>Conclusion</p> <p>Taken together, we demonstrate that blockade of mTOR and/or PI3K/Akt enhances prostanoid production and that PI3K/Akt, GSK-3 and mTOR differently regulate the expression of mPGES-1 and COX-2 in activated primary microglia. Therefore, these pathways are potential targets for the development of novel strategies to modulate neuroinflammation.</p>http://www.jneuroinflammation.com/content/9/1/2microgliaphosphatidylinositol 3-kinasemammalian target of rapamycinglycogen synthase kinase-3Aktprostaglandins |
| spellingShingle | de Oliveira Antonio CP Candelario-Jalil Eduardo Langbein Julia Wendeburg Lena Bhatia Harsharan S Schlachetzki Johannes CM Biber Knut Fiebich Bernd L Pharmacological inhibition of Akt and downstream pathways modulates the expression of COX-2 and mPGES-1 in activated microglia Journal of Neuroinflammation microglia phosphatidylinositol 3-kinase mammalian target of rapamycin glycogen synthase kinase-3 Akt prostaglandins |
| title | Pharmacological inhibition of Akt and downstream pathways modulates the expression of COX-2 and mPGES-1 in activated microglia |
| title_full | Pharmacological inhibition of Akt and downstream pathways modulates the expression of COX-2 and mPGES-1 in activated microglia |
| title_fullStr | Pharmacological inhibition of Akt and downstream pathways modulates the expression of COX-2 and mPGES-1 in activated microglia |
| title_full_unstemmed | Pharmacological inhibition of Akt and downstream pathways modulates the expression of COX-2 and mPGES-1 in activated microglia |
| title_short | Pharmacological inhibition of Akt and downstream pathways modulates the expression of COX-2 and mPGES-1 in activated microglia |
| title_sort | pharmacological inhibition of akt and downstream pathways modulates the expression of cox 2 and mpges 1 in activated microglia |
| topic | microglia phosphatidylinositol 3-kinase mammalian target of rapamycin glycogen synthase kinase-3 Akt prostaglandins |
| url | http://www.jneuroinflammation.com/content/9/1/2 |
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