title: Synergy between IL-6 and TGF-β signaling promotes FOXP3 degradation.
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.
authors.affiliation: The Bioengineering Graduate Program, School of Life Sciences, Fudan University, Shanghai, 200433, China.
authors.forename: Zhimei
authors.initials: Z
authors.lastname: Gao
authors.forename: Yayi
authors.initials: Y
authors.lastname: Gao
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Li
authors.forename: Zuojia
authors.initials: Z
authors.lastname: Chen
authors.forename: Daru
authors.initials: D
authors.lastname: Lu
authors.forename: Andy
authors.initials: A
authors.lastname: Tsun
authors.forename: Bin
authors.initials: B
authors.lastname: Li
mesh_terms: D060833:Cellular Microenvironment / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology*; D019169:Jurkat Cells; D007976:Leupeptins / Q000494:pharmacology; D059748:Proteolysis / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508600:IL6 protein, human; D015850:Interleukin-6; D007976:Leupeptins; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; D016212:Transforming Growth Factor beta; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde