Dataset Information

Cyp26b1 regulates retinoic acid-dependent signals in T cells and its expression is inhibited by transforming growth factor-?.

ABSTRACT:

Background

The vitamin A metabolite, retinoic acid (RA), plays important roles in the regulation of lymphocyte properties. Dendritic cells in gut-related lymphoid organs can produce RA, thereby imprinting gut-homing specificity on T cells and enhancing transforming growth factor (TGF)-?-dependent induction of Foxp3+ regulatory T cells upon antigen presentation. In general, RA concentrations in cells and tissues are regulated by its degradation as well. However, it remained unclear if T cells could actively catabolize RA.

Methodology/principal findings

We assessed the expression of known RA-catabolizing enzymes in T cells from mouse lymphoid tissues. Antigen-experienced CD44+ T cells in gut-related lymphoid organs selectively expressed Cyp26b1, a member of the cytochrome P450 family 26. However, T cells in the spleen or skin-draining lymph nodes did not significantly express Cyp26b1. Accordingly, physiological levels of RA (1-10 nM) could induce Cyp26b1 expression in naïve T cells upon activation in vitro, but could not do so in the presence of TGF-?. Overexpression of Cyp26b1 significantly suppressed the RA effect to induce expression of the gut-homing receptor CCR9 on T cells. On the other hand, knocking down Cyp26b1 gene expression with small interfering RNA or inhibiting CYP26 enzymatic activity led to enhancement of the RA-induced CCR9 expression.

Conclusions/significance

Our data demonstrate a role for CYP26B1 in regulating RA-dependent signals in activated T cells but not during TGF-?-dependent differentiation to Foxp3+ regulatory T cells. Aberrant expression of CYP26B1 may disturb T cell trafficking and differentiation in the gut and its related lymphoid organs.

SUBMITTER: Takeuchi H

PROVIDER: S-EPMC3017564 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Publications

Cyp26b1 regulates retinoic acid-dependent signals in T cells and its expression is inhibited by transforming growth factor-β.

Takeuchi Hajime H Yokota Aya A Ohoka Yoshiharu Y Iwata Makoto M

PloS one 20110107 1

<h4>Background</h4>The vitamin A metabolite, retinoic acid (RA), plays important roles in the regulation of lymphocyte properties. Dendritic cells in gut-related lymphoid organs can produce RA, thereby imprinting gut-homing specificity on T cells and enhancing transforming growth factor (TGF)-β-dependent induction of Foxp3+ regulatory T cells upon antigen presentation. In general, RA concentrations in cells and tissues are regulated by its degradation as well. However, it remained unclear if T c ...[more]

PMID: 21249211

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Project description:BACKGROUND: The effects of transforming growth factor-beta (TGFβ) are mediated by the transcription factors Smad2 and Smad3. During adult skeletal myogenesis, TGFβ signaling inhibits the differentiation of myoblasts, and this can be reversed by treatment with retinoic acid (RA). In mesenchymal stem cells and preadipocytes, RA treatment can function in a non-classical manner by stimulating the expression of Smad3. Smad3 can bind to and prevent the bzip transcription factor CCAAT/enhancer-binding protein beta (C/EBPβ) from binding DNA response elements in target promoters, thereby affecting cell differentiation. In skeletal muscle, C/EBPβ is highly expressed in satellite cells and myoblasts and is downregulated during differentiation. Persistent expression of C/EBPβ in myoblasts inhibits their differentiation. METHODS: Using both C2C12 myoblasts and primary myoblasts, we examined the regulation of C/EBPβ expression and activity following treatment with TGFβ and RA. RESULTS: We demonstrate that treatment with RA upregulates Smad3, but not Smad2 expression in myoblasts, and can partially rescue the block of differentiation induced by TGFβ. RA treatment reduces C/EBPβ occupancy of the Pax7 and Smad2 promoters and decreased their expression. RA also inhibits the TGFβ-mediated phosphorylation of Smad2, which may also contribute to its pro-myogenic activities. TGFβ treatment of C2C12 myoblasts stimulates C/EBPβ expression, which in turn can stimulate Pax7 and Smad2 expression, and inhibits myogenesis. Loss of C/EBPβ expression in myoblasts partially restores differentiation in the presence of TGFβ. CONCLUSIONS: TGFβ acts, at least in part, to inhibit myogenesis by upregulating the expression of C/EBPβ, as treatment with RA or loss of C/EBPβ can partially rescue differentiation in TGFβ-treated cells. This work identifies a pro-myogenic role for Smad3, through the inhibition of C/EBPβ's actions in myoblasts, and reveals mechanisms of crosstalk between RA and TGFβ signaling pathways.