Abstract
The forkhead family transcription factor FOXP3 is critical for the differentiation and function of CD4(+) CD25(+) regulatory T cells (Treg). How FOXP3 protein level is negatively regulated under the inflammatory microenvironment is largely unknown. Here we report that the combination of transforming growth factor-beta (TGF-β) and IL-6 treatment (IL-6/TGF-β) can synergistically downregulate FOXP3 at the posttranslational level by promoting FOXP3 protein degradation. In our FOXP3 overexpression model, we found that IL-6/TGF-β treatment upregulated IL-6R expression but did not affect the stability of FOXP3 mRNA. Moreover, we found that the proteasome inhibitor MG132 could inhibit IL-6/TGF-β-mediated downregulation of FOXP3 protein, which reveals a potential pathway for modulating Treg activity by preventing FOXP3 degradation during inflammation.
Keywords:
FOXP3; IL-6; TGF-β; Treg; instability; proteasome.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Cellular Microenvironment / physiology
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Down-Regulation / drug effects
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Drug Synergism
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Forkhead Transcription Factors / metabolism*
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Humans
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Inflammation / pathology
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Interleukin-6 / metabolism
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Interleukin-6 / pharmacology*
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Jurkat Cells
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Leupeptins / pharmacology
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Proteolysis / drug effects
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RNA, Messenger / metabolism
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Receptors, Interleukin-6 / biosynthesis
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Signal Transduction / drug effects*
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Signal Transduction / physiology
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T-Lymphocytes, Regulatory / drug effects
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T-Lymphocytes, Regulatory / metabolism
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Transforming Growth Factor beta / metabolism
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Transforming Growth Factor beta / pharmacology*
Substances
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FOXP3 protein, human
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Forkhead Transcription Factors
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IL6 protein, human
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Interleukin-6
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Leupeptins
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RNA, Messenger
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Receptors, Interleukin-6
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Transforming Growth Factor beta
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde