Journal
ONCOTARGET
Volume 8, Issue 30, Pages 49735-49748Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.17683
Keywords
TNF-alpha secretion; dexamethasone; innate immunity; p38 MAPK signaling; tumor necrosis factor-alpha (TNF-alpha)-converting enzyme
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Funding
- Taiwan Ministry of Science and Technology [MOST 103-2628-B-010-003-MY4, MOST 104-2923-B-010-002-MY2]
- Novel Bioengineering and Technological Approaches to Solve Two Major Health Problems in Taiwan - Taiwan Ministry of Science and Technology Academic Excellence Program [MOST 106-2633-B-009-001]
- Yen Tjing Ling Medical Foundation
- Ministry of Education's Aim for the Top University Plan
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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-alpha secretion and reveal p38 MAPK signaling as a target of Dex that is involved in control of tumor necrosis factor-a (TNF-alpha)-converting enzyme (TACE) activity; that later mediates the shedding of TNF-alpha 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-alpha secretion by activated macrophages. Blockage of the hydroxyl groups of Dex inhibits immunosuppressant effect of Dex during LPS-induced TNF-alpha secretion and mouse mortality. Our findings demonstrate Dex signaling is involved in the control of innate immunity.
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