Suppression of LPS-induced inflammatory responses by the hydroxyl groups of dexamethasone
Metrics: PDF 1044 views | HTML 1839 views | ?
Ting-Yun Chuang1, An-Jie Cheng1, I-Ting Chen1, Tien-Yun Lan1, I-Hsuan Huang1, Chung-Wai Shiau2, Chia-Lin Hsu3, Ya-Wen Liu4, Zee-Fen Chang4, Ping-Hui Tseng1 and Jean-Cheng Kuo1,5,6
1Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 11221, Taiwan
2Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 11221, Taiwan
3Institute of Microbiology and Immunology, National Yang-Ming University, Taipei 11221, Taiwan
4Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei 10002, Taiwan
5Biophotonics & Molecular Imaging Research Center, National Yang-Ming University, Taipei 11221, Taiwan
6Proteomics Research Center, National Yang-Ming University, Taipei 11221, Taiwan
Jean-Cheng Kuo, email: email@example.com
Keywords: TNF-α secretion, dexamethasone, innate immunity, p38 MAPK signaling, tumor necrosis factor-α (TNF-α)-converting enzyme
Abbreviations: Dex: dexamethasone, LPS: Lipopolysaccharide, TNF-α: Tumor necrosis factor-α, TACE: Tumor necrosis factor-α (TNF-α)-converting enzyme
Received: October 26, 2016 Accepted: April 15, 2017 Published: May 08, 2017
The innate immune response is a central process that is activated during pathogenic infection in order to maintain physiological homeostasis. It is well known that dexamethasone (Dex), a synthetic glucocorticoid, is a potent immunosuppressant that inhibits the cytokine production induced by bacterial lipopolysaccharides (LPS). Nevertheless, the extent to which the functional groups of Dex control the excessive activation of inflammatory reactions remains unknown. Furthermore, importantly, the role of Dex in the innate immune response remains unclear. Here we explore the mechanism of LPS-induced TNF-α secretion and reveal p38 MAPK signaling as a target of Dex that is involved in control of tumor necrosis factor-α (TNF-α)-converting enzyme (TACE) activity; that later mediates the shedding of TNF-α that allows its secretion. We further demonstrate that the 11-hydroxyl and 21-hydroxyl groups of Dex are the main groups that are involved in reducing LPS-induced TNF-α secretion by activated macrophages. Blockage of the hydroxyl groups of Dex inhibits immunosuppressant effect of Dex during LPS-induced TNF-α secretion and mouse mortality. Our findings demonstrate Dex signaling is involved in the control of innate immunity.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.