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

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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-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.

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Acknowledgments

This work was supported by research grants from Taichung Veterans General Hospital, Taiwan (TCVGH-977304B), and the National Science Council of Taiwan (NSC96-2320-B-040-003-MY3).

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Authors and Affiliations

  1. Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan

    Shing Hwa Liu

  2. Institute of Neuroscience, School of Life Science, National Yang-Ming University, Taipei, Taiwan

    Cheng Ning Yang

  3. Department of Neurosurgery, Taichung Veterans General Hospital, Taichung, Taiwan

    Hung Chuan Pan

  4. Institute of Medical Technology, National Chung Hsing University, 250 Kuo Kuang Road, Taichung, 402, Taiwan

    Hung Chuan Pan, Wen Bao Chen, Wen Zheng Lin & Meei Ling Sheu

  5. Institute of Anatomy and Cell Biology, School of Life Science, National Yang-Ming University, Taipei, Taiwan

    Yen Jen Sung

  6. Department of Anatomy, Chung Shan Medical University, Taichung, Taiwan

    Ko Kaung Liao

  7. Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan

    Meei Ling Sheu

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  1. Shing Hwa Liu
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Correspondence to Meei Ling Sheu.

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S. H. Liu, C. N. Yang, and H. C. Pan contributed equally to this work.

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Liu, S.H., Yang, C.N., Pan, H.C. et al. IL-13 downregulates PPAR-γ/heme oxygenase-1 via ER stress-stimulated calpain activation: aggravation of activated microglia death. Cell. Mol. Life Sci. 67, 1465–1476 (2010). https://doi.org/10.1007/s00018-009-0255-4

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