Abstract
Systemic lupus erythematosus (SLE) damages multiple organs by producing various autoantibodies. In this study, we report that decreased microRNA (miR)-200a-3p causes IL-2 hypoproduction through zinc finger E-box binding homeobox (ZEB)1 and C-terminal binding protein 2 (CtBP2) in a lupus-prone mouse. First, we performed RNA sequencing to identify candidate microRNAs and mRNAs involved in the pathogenesis of SLE. We found that miR-200a-3p was significantly downregulated, whereas its putative targets, ZEB2 and CtBP2, were upregulated in CD4+T cells from MRL/lpr-Tnfrsf6lpr mice compared with C57BL/6J mice. ZEB1 and ZEB2 comprise the ZEB family and suppress various genes, including IL-2 by recruiting CtBP2. IL-2 plays a critical role in immune tolerance, and insufficient IL-2 production upon stimulation has been recognized in SLE pathogenesis. Therefore, we hypothesized that decreased miR-200a-3p causes IL-2 deficit through the ZEB1-CtBP2 and/or ZEB2-CtBP2 complex in SLE CD4+T cells. Overexpression of miR-200a-3p induced IL-2 production by downregulating ZEB1, ZEB2, and CtBP2 in EL4 cell lines. We further revealed that miR-200a-3p promotes IL-2 expression by reducing the binding of suppressive ZEB1-CtBP2 and ZEB2-CtBP2 complexes on negative regulatory element A in the IL-2 promoter in EL4 cells. Interestingly, the ZEB1-CtBP2 complex on negative regulatory element Awas significantly upregulated after PMA/ionomycin stimulation in lupus CD4+T cells. Our studies have revealed a new epigenetic pathway in the control of IL-2 production in SLE whereby low levels of miR-200a-3p accumulate the binding of the ZEB1-CtBP2 complex to the IL-2 promoter and suppress IL-2 production.
| Original language | English |
|---|---|
| Pages (from-to) | 4268-4276 |
| Number of pages | 9 |
| Journal | Journal of Immunology |
| Volume | 198 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - Jun 1 2017 |
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ASJC Scopus subject areas
- Immunology
Cite this
Downregulation of miR-200a-3p, targeting CtBP2 complex, is involved in the hypoproduction of IL-2 in systemic lupus erythematosus-derived T cells. / Katsuyama, Eri; Yan, Minglu; Watanabe, Katsue Sunahori; Matsushima, Syun; Yamamura, Yuriko; Hiramatsu, Sumie; Ohashi, Keiji; Watanabe, Haruki; Katsuyama, Takayuki; Zeggar, Sonia; Yoshida, Nobuya; Moulton, Vaishali R.; Tsokos, George C.; Sada, Kenei; Wada, Jun.
In: Journal of Immunology, Vol. 198, No. 11, 01.06.2017, p. 4268-4276.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Downregulation of miR-200a-3p, targeting CtBP2 complex, is involved in the hypoproduction of IL-2 in systemic lupus erythematosus-derived T cells
AU - Katsuyama, Eri
AU - Yan, Minglu
AU - Watanabe, Katsue Sunahori
AU - Matsushima, Syun
AU - Yamamura, Yuriko
AU - Hiramatsu, Sumie
AU - Ohashi, Keiji
AU - Watanabe, Haruki
AU - Katsuyama, Takayuki
AU - Zeggar, Sonia
AU - Yoshida, Nobuya
AU - Moulton, Vaishali R.
AU - Tsokos, George C.
AU - Sada, Kenei
AU - Wada, Jun
PY - 2017/6/1
Y1 - 2017/6/1
N2 - Systemic lupus erythematosus (SLE) damages multiple organs by producing various autoantibodies. In this study, we report that decreased microRNA (miR)-200a-3p causes IL-2 hypoproduction through zinc finger E-box binding homeobox (ZEB)1 and C-terminal binding protein 2 (CtBP2) in a lupus-prone mouse. First, we performed RNA sequencing to identify candidate microRNAs and mRNAs involved in the pathogenesis of SLE. We found that miR-200a-3p was significantly downregulated, whereas its putative targets, ZEB2 and CtBP2, were upregulated in CD4+T cells from MRL/lpr-Tnfrsf6lpr mice compared with C57BL/6J mice. ZEB1 and ZEB2 comprise the ZEB family and suppress various genes, including IL-2 by recruiting CtBP2. IL-2 plays a critical role in immune tolerance, and insufficient IL-2 production upon stimulation has been recognized in SLE pathogenesis. Therefore, we hypothesized that decreased miR-200a-3p causes IL-2 deficit through the ZEB1-CtBP2 and/or ZEB2-CtBP2 complex in SLE CD4+T cells. Overexpression of miR-200a-3p induced IL-2 production by downregulating ZEB1, ZEB2, and CtBP2 in EL4 cell lines. We further revealed that miR-200a-3p promotes IL-2 expression by reducing the binding of suppressive ZEB1-CtBP2 and ZEB2-CtBP2 complexes on negative regulatory element A in the IL-2 promoter in EL4 cells. Interestingly, the ZEB1-CtBP2 complex on negative regulatory element Awas significantly upregulated after PMA/ionomycin stimulation in lupus CD4+T cells. Our studies have revealed a new epigenetic pathway in the control of IL-2 production in SLE whereby low levels of miR-200a-3p accumulate the binding of the ZEB1-CtBP2 complex to the IL-2 promoter and suppress IL-2 production.
AB - Systemic lupus erythematosus (SLE) damages multiple organs by producing various autoantibodies. In this study, we report that decreased microRNA (miR)-200a-3p causes IL-2 hypoproduction through zinc finger E-box binding homeobox (ZEB)1 and C-terminal binding protein 2 (CtBP2) in a lupus-prone mouse. First, we performed RNA sequencing to identify candidate microRNAs and mRNAs involved in the pathogenesis of SLE. We found that miR-200a-3p was significantly downregulated, whereas its putative targets, ZEB2 and CtBP2, were upregulated in CD4+T cells from MRL/lpr-Tnfrsf6lpr mice compared with C57BL/6J mice. ZEB1 and ZEB2 comprise the ZEB family and suppress various genes, including IL-2 by recruiting CtBP2. IL-2 plays a critical role in immune tolerance, and insufficient IL-2 production upon stimulation has been recognized in SLE pathogenesis. Therefore, we hypothesized that decreased miR-200a-3p causes IL-2 deficit through the ZEB1-CtBP2 and/or ZEB2-CtBP2 complex in SLE CD4+T cells. Overexpression of miR-200a-3p induced IL-2 production by downregulating ZEB1, ZEB2, and CtBP2 in EL4 cell lines. We further revealed that miR-200a-3p promotes IL-2 expression by reducing the binding of suppressive ZEB1-CtBP2 and ZEB2-CtBP2 complexes on negative regulatory element A in the IL-2 promoter in EL4 cells. Interestingly, the ZEB1-CtBP2 complex on negative regulatory element Awas significantly upregulated after PMA/ionomycin stimulation in lupus CD4+T cells. Our studies have revealed a new epigenetic pathway in the control of IL-2 production in SLE whereby low levels of miR-200a-3p accumulate the binding of the ZEB1-CtBP2 complex to the IL-2 promoter and suppress IL-2 production.
UR - http://www.scopus.com/inward/record.url?scp=85019873437&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85019873437&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1601705
DO - 10.4049/jimmunol.1601705
M3 - Article
C2 - 28438897
AN - SCOPUS:85019873437
VL - 198
SP - 4268
EP - 4276
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 11
ER -