title: Reciprocal modulation of C/EBP-α and C/EBP-β by IL-13 in activated microglia prevents neuronal death.
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.
authors.affiliation: Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Neurosurgery, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Hung Chuan
authors.initials: HC
authors.lastname: Pan
authors.forename: Cheng Ning
authors.initials: CN
authors.lastname: Yang
authors.forename: Yi Wen
authors.initials: YW
authors.lastname: Hung
authors.forename: Wen Jane
authors.initials: WJ
authors.lastname: Lee
authors.forename: Hsing Ru
authors.initials: HR
authors.lastname: Tien
authors.forename: Chin Chang
authors.initials: CC
authors.lastname: Shen
authors.forename: Jason
authors.initials: J
authors.lastname: Sheehan
authors.forename: Chiang Ting
authors.initials: CT
authors.lastname: Chou
authors.forename: Meei Ling
authors.initials: ML
authors.lastname: Sheu
mesh_terms: D000818:Animals; D017209:Apoptosis; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D022762:CCAAT-Enhancer-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism; D053454:Caspase 12 / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D018793:Interleukin-13 / Q000378:metabolism*; D008070:Lipopolysaccharides; D008565:Membrane Proteins / Q000096:biosynthesis; D017628:Microglia / Q000378:metabolism*; D009474:Neurons / Q000502:physiology*; D047495:PPAR gamma / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D015398:Signal Transduction
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D022762:CCAAT-Enhancer-Binding Proteins; C530718:CEBPA protein, mouse; C545013:Cebpb protein, mouse; D018793:Interleukin-13; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D047495:PPAR gamma; D034741:RNA, Small Interfering; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D002154:Calpain; C506443:Casp12 protein, rat; D053454:Caspase 12; D015232:Dinoprostone
keywords: C/EBP; IL-13; Microglia; Neuron