Abstract
BackgroundMicroglia 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.FindingsWe 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 non-stimulated microglia.ConclusionTaken 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.
Highlights
Microglia are considered a major target for modulating neuroinflammatory and neurodegenerative disease processes
Taken together, we demonstrate that blockade of mammalian target of rapamycin (mTOR) and/or phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) enhances prostanoid production and that PI3K/Akt, glycogen synthase kinase-3 (GSK-3) and mTOR differently regulate the expression of microsomal prostaglandin E synthase (mPGES)-1 and COX-2 in activated primary microglia
The phosphorylation on the respective residues of Akt leads to further catalytic activity changes of downstream targets, such as glycogen synthase kinase-3 (GSK-3) and mammalian target of rapamycin [3,4]
Summary
Microglia are considered a major target for modulating neuroinflammatory and neurodegenerative disease processes. 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. Akt inhibitor X slightly increased COX-2 and reduced mPGES-1 protein levels induced by LPS, without reaching statistical difference (Figure 1A-B).
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