IL-13 downregulates PPAR-gamma/heme oxygenase-1 via ER stress-stimulated calpain activation: aggravation of activated microglia death.
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.
Liu
Shing Hwa
SH
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan. shinghwaliu@ntu.edu.tw
Yang
Cheng Ning
CN
Pan
Hung Chuan
HC
Sung
Yen Jen
YJ
Liao
Ko Kaung
KK
Chen
Wen Bao
WB
Lin
Wen Zheng
WZ
Sheu
Meei Ling
ML
D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004789:Enzyme Activation; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological
D018793:Interleukin-13; D007527:Isoenzymes; D008070:Lipopolysaccharides; D047495:PPAR gamma; D034741:RNA, Small Interfering; D051547:Heme Oxygenase-1; D002154:Calpain