Reciprocal modulation of C/EBP‐α and C/EBP‐β by IL‐13 in activated microglia prevents neuronal death |
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| Authors: | 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 |
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| Institution: | 1. Faculty of Medicine, School of Medicine, National Yang‐Ming University, , Taipei, Taiwan;2. Department of Neurosurgery, Taichung Veterans General Hospital, , Taichung, Taiwan;3. Institute of Neuroscience, School of Life Science, National Yang‐Ming University, , Taipei, Taiwan;4. Department of Education and Research, Taichung Veterans General Hospital, , Taichung, Taiwan;5. Department of Veterinary Medicine, College of Veterinary Medicine, National Chung Hsing University, , Taichung, Taiwan;6. Institute of Biomedical Sciences, College of Life Science, National Chung Hsing University, , Taichung, Taiwan;7. Institute of Nuclear Energy Research, Atomic Energy Council, , Longtan, Taoyuan, Taiwan;8. Department of Neurological Surgery, University of Virginia Health System, , Charlottesville, VA, USA;9. School of Nursing, Chang Gung University of Science and Technology, , Chiayi Campus, Taiwan |
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| Abstract: | 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. |
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| Keywords: | C/EBP IL‐13 Microglia Neuron |
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