抄録
Mutations of DOCK8 in humans cause a combined immunodeficiency characterized by atopic dermatitis with high serum IgE levels. However, the molecular link between DOCK8 deficiency and atopic skin inflammation is unknown. Here we show that CD4+ T cells from DOCK8-deficient mice produce large amounts of IL-31, a major pruritogen associated with atopic dermatitis. IL-31 induction critically depends on the transcription factor EPAS1, and its conditional deletion in CD4+ T cells abrogates skin disease development in DOCK8-deficient mice. Although EPAS1 is known to form a complex with aryl hydrocarbon receptor nuclear translocator (ARNT) and control hypoxic responses, EPAS1-mediated Il31 promoter activation is independent of ARNT, but in collaboration with SP1. On the other hand, we find that DOCK8 is an adaptor and negative regulator of nuclear translocation of EPAS1. Thus, EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction in CD4+ T cells.
| 元の言語 | 英語 |
|---|---|
| 記事番号 | 13946 |
| ジャーナル | Nature communications |
| 巻 | 8 |
| DOI | |
| 出版物ステータス | 出版済み - 1 9 2017 |
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All Science Journal Classification (ASJC) codes
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)
これを引用
The transcription factor EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction. / Yamamura, Kazuhiko; Uruno, Takehito; Shiraishi, Akira; Tanaka, Yoshihiko; Ushijima, Miho; Nakahara, Takeshi; Watanabe, Mayuki; Kido-Nakahara, Makiko; Tsuge, Ikuya; Furue, Masutaka; Fukui, Yoshinori.
：: Nature communications, 巻 8, 13946, 09.01.2017.研究成果: ジャーナルへの寄稿 › 記事
}
TY - JOUR
T1 - The transcription factor EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction
AU - Yamamura, Kazuhiko
AU - Uruno, Takehito
AU - Shiraishi, Akira
AU - Tanaka, Yoshihiko
AU - Ushijima, Miho
AU - Nakahara, Takeshi
AU - Watanabe, Mayuki
AU - Kido-Nakahara, Makiko
AU - Tsuge, Ikuya
AU - Furue, Masutaka
AU - Fukui, Yoshinori
PY - 2017/1/9
Y1 - 2017/1/9
N2 - Mutations of DOCK8 in humans cause a combined immunodeficiency characterized by atopic dermatitis with high serum IgE levels. However, the molecular link between DOCK8 deficiency and atopic skin inflammation is unknown. Here we show that CD4+ T cells from DOCK8-deficient mice produce large amounts of IL-31, a major pruritogen associated with atopic dermatitis. IL-31 induction critically depends on the transcription factor EPAS1, and its conditional deletion in CD4+ T cells abrogates skin disease development in DOCK8-deficient mice. Although EPAS1 is known to form a complex with aryl hydrocarbon receptor nuclear translocator (ARNT) and control hypoxic responses, EPAS1-mediated Il31 promoter activation is independent of ARNT, but in collaboration with SP1. On the other hand, we find that DOCK8 is an adaptor and negative regulator of nuclear translocation of EPAS1. Thus, EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction in CD4+ T cells.
AB - Mutations of DOCK8 in humans cause a combined immunodeficiency characterized by atopic dermatitis with high serum IgE levels. However, the molecular link between DOCK8 deficiency and atopic skin inflammation is unknown. Here we show that CD4+ T cells from DOCK8-deficient mice produce large amounts of IL-31, a major pruritogen associated with atopic dermatitis. IL-31 induction critically depends on the transcription factor EPAS1, and its conditional deletion in CD4+ T cells abrogates skin disease development in DOCK8-deficient mice. Although EPAS1 is known to form a complex with aryl hydrocarbon receptor nuclear translocator (ARNT) and control hypoxic responses, EPAS1-mediated Il31 promoter activation is independent of ARNT, but in collaboration with SP1. On the other hand, we find that DOCK8 is an adaptor and negative regulator of nuclear translocation of EPAS1. Thus, EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction in CD4+ T cells.
UR - http://www.scopus.com/inward/record.url?scp=85009154922&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85009154922&partnerID=8YFLogxK
U2 - 10.1038/ncomms13946
DO - 10.1038/ncomms13946
M3 - Article
C2 - 28067314
AN - SCOPUS:85009154922
VL - 8
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 13946
ER -