Prostaglandin E2 released from activated microglia enhances astrocyte proliferation in vitro

Abstract

Microglial activation has been implicated in many astrogliosis-related pathological conditions including astroglioma; however, the detailed mechanism is not clear. In this study, we used primary enriched microglia and astrocytes cultures to determine the role of microglial prostaglandin E2 (PGE2) in the proliferation of astrocytes. The proliferation of astrocytes was measured by BrdU incorporation. The level of PGE2 was measured by ELISA method. Pharmacological inhibition or genetic ablation of COX-2 in microglia were also applied in this study. We found that proliferation of astrocytes increased following lipopolysaccharide (LPS) treatment in the presence of microglia. Furthermore, increased proliferation of astrocytes was observed in the presence of conditioned media from LPS-treated microglia. The potential involvement of microglial PGE2 in enhanced astrocyte proliferation was suggested by the findings that PGE2 production and COX-2 expression in microglia were increased by LPS treatment. In addition, activated microglia-induced increases in astrocyte proliferation were blocked by the PGE2 antagonist AH6809, COX-2 selective inhibitor DuP-697 or by genetic knockout of microglial COX-2. These findings were further supported by the finding that addition of PGE2 to the media significantly induced astrocyte proliferation. These results indicate that microglial PGE2 plays an important role in astrocyte proliferation, identifying PGE2 as a key neuroinflammatory molecule that triggers the pathological response related to uncontrollable astrocyte proliferation. These findings are important in elucidating the role of activated microglia and PGE2 in astrocyte proliferation and in suggesting a potential avenue in the use of anti-inflammatory agents for the therapy of astroglioma.

Doxycycline is Neuroprotective Against Nigral Dopaminergic Degeneration by a Dual Mechanism Involving MMP-3

“…Astrogliosis in the MPTP-treated animals was also found to be suppressed by the doxycycline co-treatment. It is possible that the soluble factors that are released from activated microglia and stimulate astrogliosis (Mohri et al 2006;Röhl et al 2007;Zhang et al 2009) are reduced under the condition that microglia activation is suppressed by the doxycycline administration.…”

The role of inflammatory processes in Alzheimer’s disease

“…It has been suggested that microglial activation precedes astroglial activation in AD (Zhang et al 2009). At the same time, it has also been suggested that the precipitating event in astrocytic activation is the formation of fibrillar Ab (Paris et al 2002b;Hensley et al 1998).…”

Quercetin ameliorates inflammation in CA1 hippocampal region in aged triple transgenic Alzheimer´s disease mice model.

“…For this reason, IL-1β stimulates the production of COX-2 by microglial cells in brains affected by Alzheimer's disease (23), which favors the expression of iNOS through PGE 2 production (24), although IL-1β also directly activates before iNOS (7). In a positive feedback, PGE 2 also induces microgliosis and this promotes astrocyte proliferation (13). Recently, it was found that microglial-specific deletion of PGE 2 restores microglial chemotaxis and βA clearance suppresses toxicity of the exacerbated pro-inflammatory response and microglial activation (25,26).…”

“…COX-2 is an inducible enzyme in pathological conditions and it catalyzes the synthesis of prostaglandins, many of which are neurotoxic, such as prostaglandin E 2 (PGE 2 ), which is the main produced inflammatory prostaglandin (12). βA peptides induce the activation of PGE 2 in astrocytes and microglia (6,12), which can produce an increase in astrocyte proliferation in vivo and diminish the ability of microglia to phagocytose βA peptides (13,14).…”