IL-13 downregulates PPAR-γ/heme oxygenase-1 via ER stress-stimulated calpain activation: aggravation of activated microglia death

• Published in: Cellular and molecular life sciences : CMLS 2010-05, Vol.67 (9), p.1465-1476
• Main Authors: Liu, Shing Hwa, Yang, Cheng Ning, Pan, Hung Chuan, Sung, Yen Jen, Liao, Ko Kaung, Chen, Wen Bao, Lin, Wen Zheng, Sheu, Meei Ling
• Format: Article
• Language: English
• Subjects: Animals; Biochemistry; Biomedical and Life Sciences; Biomedicine; Calpain - antagonists & inhibitors; Calpain - genetics; Calpain - metabolism; Cell Biology; Cell Death - physiology; Cells, Cultured; Endoplasmic Reticulum - metabolism; Enzyme Activation; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Interleukin-13 - genetics; Interleukin-13 - metabolism; Isoenzymes - antagonists & inhibitors; Isoenzymes - genetics; Isoenzymes - metabolism; Life Sciences; Lipopolysaccharides - pharmacology; Mice; Microglia - cytology; Microglia - drug effects; Microglia - pathology; Microglia - physiology; PPAR gamma - genetics; PPAR gamma - metabolism; Rats; Rats, Sprague-Dawley; Research Article; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Stress, Physiological
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-009-0255-4

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-γ (PPAR-γ) was also increased in activated microglia, and this was effectively blocked by IL-13 and recombinant calpain. Both HO-1 inhibitor and PPAR-γ antagonist augmented, but calpain inhibitor and PPAR-γ agonists reversed, apoptosis induction in activated microglia. Transfection of PPAR-γ siRNA effectively inhibited HO-1 protein expression in activated microglia. LPS stimulated transcriptional activation of HO-1 via an increase in PPAR-γ DNA binding activity, which was reversed by IL-13. These results indicate that an ER stress-related calpain-down-regulated PPAR-γ/HO-1 pathway is involved in the IL-13-enhanced activated death of microglia.