Pharmacological inhibition of Akt and downstream pathways modulates the expression of COX-2 and mPGES-1 in activated mic
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SHORT REPORT
JOURNAL OF NEUROINFLAMMATION
Open Access
Pharmacological inhibition of Akt and downstream pathways modulates the expression of COX-2 and mPGES-1 in activated microglia Antonio CP de Oliveira1,2, Eduardo Candelario-Jalil1,3, Julia Langbein1, Lena Wendeburg1, Harsharan S Bhatia1, Johannes CM Schlachetzki1,4, Knut Biber1 and Bernd L Fiebich1,5*
Abstract Background: 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) E2 and PGD2. Findings: We show that inhibition of Akt by the Akt inhibitor X enhanced the production of PGE2 and PGD2 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 PGE2 and PGD2. Interestingly, NVP-BEZ235, a dual PI3K/mTOR inhibitor, enhanced COX-2 and reduced mPGES-1 immunoreactivity, albeit PGE2 and PGD2 levels were enhanced in LPS-stimulated microglia. However, this compound also increased PGE2 in nonstimulated microglia. Conclusion: 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. Keywords: microglia, phosphatidylinositol 3-kinase, mammalian target of rapamycin, glycogen synthase kinase-3, Akt, prostaglandins
Findings Inflammation has been recognized not only as a mere bystander in neurodegenerative diseases but also as a factor driving disease progression. Microglia, the innate phagocytic cells of the central nervous system (CNS), constantly survey their microenvironment. Activated * Correspondence: [email protected] 1 Department of Psychiatry and Psychotherapy, University of Freiburg Medical School, Hauptstr. 5, D-79104 Freiburg, Germany Full list of author information is available at the end of the article
microglia secrete inflammatory
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