1. IL-13 downregulates PPAR-gamma/heme oxygenase-1 via ER stress-stimulated calpain activation: aggravation of activated microglia death.
- Author
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Liu SH, Yang CN, Pan HC, Sung YJ, Liao KK, Chen WB, Lin WZ, and Sheu ML
- Subjects
- Animals, Calpain antagonists & inhibitors, Calpain genetics, Cell Death physiology, Cells, Cultured, Enzyme Activation, Heme Oxygenase-1 genetics, Interleukin-13 genetics, Isoenzymes antagonists & inhibitors, Isoenzymes genetics, Lipopolysaccharides pharmacology, Mice, Microglia cytology, Microglia drug effects, Microglia pathology, PPAR gamma genetics, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, Rats, Rats, Sprague-Dawley, Calpain metabolism, Endoplasmic Reticulum metabolism, Heme Oxygenase-1 metabolism, Interleukin-13 metabolism, Isoenzymes metabolism, Microglia physiology, PPAR gamma metabolism, Stress, Physiological
- Abstract
Interleukin 13 (IL-13) has been shown to induce the death of activated microglia. We observed that IL-13, but not IL-4 or IL-10, significantly enhanced endoplasmic reticulum (ER) stress induction, apoptosis and death in microglia activated by lipopolysaccharide (LPS). IL-13 enhanced ER stress-regulated calpain activation and calpain-II expression in LPS-activated microglia. Calpain-II siRNA effectively reversed the IL-13 + LPS-activated caspase-12 activation. Expression of heme oxygenase-1 (HO-1) and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) was also increased in activated microglia, and this was effectively blocked by IL-13 and recombinant calpain. Both HO-1 inhibitor and PPAR-gamma antagonist augmented, but calpain inhibitor and PPAR-gamma agonists reversed, apoptosis induction in activated microglia. Transfection of PPAR-gamma siRNA effectively inhibited HO-1 protein expression in activated microglia. LPS stimulated transcriptional activation of HO-1 via an increase in PPAR-gamma DNA binding activity, which was reversed by IL-13. These results indicate that an ER stress-related calpain-down-regulated PPAR-gamma/HO-1 pathway is involved in the IL-13-enhanced activated death of microglia.
- Published
- 2010
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