[Show abstract][Hide abstract] ABSTRACT:
In response to aggravation by activated microglia, IL-13 can significantly enhance endoplasmic reticulum stress induction, apoptosis, and death via reciprocal signaling through C/EBPα and C/EBPβ. This reciprocal signaling promotes neuronal survival. Since the induction of COX-2 and PPARγ/HO-1 by IL-13 plays a crucial role in the promotion of and protection from activated microglia respectively, here we investigated the role of IL-13 in regulating C/EBPs in activated microglia and determined its correlation with neuronal function. The results revealed that IL-13 significantly enhanced C/EBPα/COX-2 expression and PGE2 production in LPS-treated microglial cells. Paradoxically, IL-13 abolished C/EBPβ/PPARγ/HO-1 expression. IL-13 also enhanced ER stress-evoked calpain activation by promoting the association of C/EBPβ and PPARγ. SiRNA-C/EBPα effectively reversed the combined LPS-activated caspase-12 activation and IL-13-induced apoptosis. In contrast, siRNA-C/EBPβ partially increased microglial cell apoptosis. By NeuN immunochemistry and CD11b staining, there was improvement in the loss of CA3 neuronal cells after intra-hippocampal injection of IL-13. This suggests that IL-13-enhanced PLA2 activity regulates COX-2/PGE2 expression through C/EBPα activation. In parallel, ER stress-related calpain downregulates the PPARγ/HO-1 pathway via C/EBPβ and leads to aggravated death of activated microglia via IL-13, thereby preventing cerebral inflammation and neuronal injury. This article is protected by copyright. All rights reserved.
European Journal of Immunology 11/2013; 43(11). DOI:10.1002/eji.201343301 · 4.52 Impact Factor