Reciprocal modulation of C/EBP-α and C/EBP-β by IL-13 in activated microglia prevents neuronal death.

Hung Chuan Pan, Cheng Ning Yang, Yi Wen Hung, Wen Jane Lee, Hsing Ru Tien, Chin Chang Shen, Jason Sheehan, Chiang Ting Chou, Meei Ling Sheu

European journal of immunology 2013 Nov

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In response to aggravation by activated microglia, IL-13 can significantly enhance ER stress induction, apoptosis, and death via reciprocal signaling through CCAAT/enhancer-binding protein alpha (C/EBP-α) and C/EBP-beta (C/EBP-β). This reciprocal signaling promotes neuronal survival. Since the induction of cyclooxygenase-2 (COX-2) and peroxisome proliferator-activated receptor gamma/heme oxygenase 1 (PPAR-γ/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/EBP-α/COX-2 expression and PGE2 production in LPS-treated microglial cells. Paradoxically, IL-13 abolished C/EBP-β/PPAR-γ/HO-1 expression. IL-13 also enhanced ER stress-evoked calpain activation by promoting the association of C/EBP-β and PPAR-γ. SiRNA-C/EBP-α effectively reversed the combined LPS-activated caspase-12 activation and IL-13-induced apoptosis. In contrast, siRNA-C/EBP-β partially increased microglial cell apoptosis. By NeuN immunochemistry and CD11b staining, there was improvement in the loss of CA3 neuronal cells after intrahippocampal injection of IL-13. This suggests that IL-13-enhanced PLA2 activity regulates COX-2/PGE2 expression through C/EBP-α activation. In parallel, ER stress-related calpain downregulates the PPAR-γ/HO-1 pathway via C/EBP-β and leads to aggravated death of activated microglia via IL-13, thereby preventing cerebral inflammation and neuronal injury. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Citation

Hung Chuan Pan, Cheng Ning Yang, Yi Wen Hung, Wen Jane Lee, Hsing Ru Tien, Chin Chang Shen, Jason Sheehan, Chiang Ting Chou, Meei Ling Sheu. Reciprocal modulation of C/EBP-α and C/EBP-β by IL-13 in activated microglia prevents neuronal death. European journal of immunology. 2013 Nov;43(11):2854-65