Abstract
Notch signaling plays an important role in differentiation of T cells. However, little is known as to action of it in differentiation of Th17 cell subset. In this study, a soluble Jagged-1/Fc chimera protein (Jagged-1) was directly used to activate Jagged-1-Notch signaling, while Hes-1-targeting siRNA was used to knock down Hes-1 gene to investigate effect of Jagged-1-Hes-1 signaling on the differentiation of CD4+ T cells into Th17 cells. The results showed that Jagged-1 could promote the expression of Hes-1 and Deltex-1 mRNAs and the expression of NICD, Hes-1 and Deltex-1 proteins, which might be significantly blocked by DAPT, a specific inhibitor of Notch signaling. Jagged-1-Hes-1 signaling resulted in the markedly decreased in situ expression of RORgammat in the CD4+ T cells induced by IL-6 plus TGF-ß. Flow cytometric analysis showed the reduction of IL-17 production in CD4+ T cells by Jagged-1, but the enhancement of it by Hes-1-targeting siRNA. The level of IL-10 produced by the treated cells was also enhanced, whereas the expression of IL-17 was prominently attenuated, which could be offset by anti-Jagged-1 antibody or DAPT. The results indicate that Jagged-1-Hes-1 signaling can suppress the skewing of CD4+ T cells toward Th17 cells via RORgammat, for which Hes-1 may be crucial.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism*
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Calcium-Binding Proteins / metabolism*
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Cell Differentiation* / drug effects
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Cell Differentiation* / genetics
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Gene Expression Regulation / drug effects
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Gene Knockdown Techniques
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism*
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Intercellular Signaling Peptides and Proteins / metabolism*
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Interleukin-17 / pharmacology
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Interleukin-6 / pharmacology
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Jagged-1 Protein
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Male
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Membrane Proteins / metabolism*
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Mice
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Mice, Inbred BALB C
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Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Small Interfering / metabolism
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Receptors, Notch / chemistry
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Receptors, Notch / metabolism
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Serrate-Jagged Proteins
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Signal Transduction* / drug effects
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Th17 Cells / cytology*
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Th17 Cells / drug effects
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Th17 Cells / metabolism
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Transcription Factor HES-1
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Transforming Growth Factor beta / pharmacology
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Ubiquitin-Protein Ligases
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Calcium-Binding Proteins
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DNA-Binding Proteins
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Hes1 protein, mouse
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Homeodomain Proteins
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Intercellular Signaling Peptides and Proteins
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Interleukin-17
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Interleukin-6
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Jag1 protein, mouse
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Jagged-1 Protein
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Membrane Proteins
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Nuclear Receptor Subfamily 1, Group F, Member 3
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RNA, Messenger
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RNA, Small Interfering
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Receptors, Notch
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Serrate-Jagged Proteins
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Transcription Factor HES-1
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Transforming Growth Factor beta
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Dtx1 protein, mouse
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Ubiquitin-Protein Ligases