IL-13 downregulates PPAR-[gamma]/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
• 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: Cellular biology; Cytokines; Inhibitor drugs; Molecular biology; Mortality; Stress
• 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-[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. [PUBLICATION ABSTRACT]