Growth Factor Midkine Promotes T-Cell Activation through Nuclear Factor of Activated T Cells Signaling and Th1 Cell Differentiation in Lupus Nephritis

Tomohiro Masuda, Kayaho Maeda, Waichi Sato, Tomoki Kosugi, Yuka Sato, Hiroshi Kojima, Noritoshi Kato, Takuji Ishimoto, Naotake Tsuboi, Kenji Uchimura, Yukio Yuzawa, Shoichi Maruyama, Kenji Kadomatsu

研究成果: Article

6 引用 (Scopus)

抄録

Activated T cells play crucial roles in the pathogenesis of autoimmune diseases, including lupus nephritis (LN). The activation of calcineurin/nuclear factor of activated T cells (NFAT) and STAT4 signaling is essential for T cells to perform various effector functions. Here, we identified the growth factor midkine (MK; gene name, Mdk) as a novel regulator in the pathogenesis of 2,6,10,14-tetramethylpentadecane-induced LN via activation of NFAT and IL-12/STAT4 signaling. Wild-type (Mdk+/+) mice showed more severe glomerular injury than MK-deficient (Mdk−/−) mice, as demonstrated by mesangial hypercellularity and matrix expansion, and glomerular capillary loops with immune-complex deposition. Compared with Mdk−/− mice, the frequency of splenic CD69+ T cells and T helper (Th) 1 cells, but not of regulatory T cells, was augmented in Mdk+/+ mice in proportion to LN disease activity, and was accompanied by skewed cytokine production. MK expression was also enhanced in activated CD4+ T cells in vivo and in vitro. MK induced activated CD4+ T cells expressing CD69 through nuclear activation of NFAT transcription and selectively increased in vitro differentiation of naive CD4+ T cells into Th1 cells by promoting IL-12/STAT4 signaling. These results suggest that MK serves an indispensable role in the NFAT-regulated activation of CD4+ T cells and Th1 cell differentiation, eventually leading to the exacerbation of LN.

元の言語English
ページ(範囲)740-751
ページ数12
ジャーナルAmerican Journal of Pathology
187
発行部数4
DOI
出版物ステータスPublished - 01-04-2017

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NFATC Transcription Factors
Th1 Cells
Lupus Nephritis
Cell Differentiation
Intercellular Signaling Peptides and Proteins
T-Lymphocytes
Interleukin-12
Calcineurin
Regulatory T-Lymphocytes
midkine
Antigen-Antibody Complex
Autoimmune Diseases
Names
Cytokines
Wounds and Injuries

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

これを引用

Masuda, Tomohiro ; Maeda, Kayaho ; Sato, Waichi ; Kosugi, Tomoki ; Sato, Yuka ; Kojima, Hiroshi ; Kato, Noritoshi ; Ishimoto, Takuji ; Tsuboi, Naotake ; Uchimura, Kenji ; Yuzawa, Yukio ; Maruyama, Shoichi ; Kadomatsu, Kenji. / Growth Factor Midkine Promotes T-Cell Activation through Nuclear Factor of Activated T Cells Signaling and Th1 Cell Differentiation in Lupus Nephritis. :: American Journal of Pathology. 2017 ; 巻 187, 番号 4. pp. 740-751.
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title = "Growth Factor Midkine Promotes T-Cell Activation through Nuclear Factor of Activated T Cells Signaling and Th1 Cell Differentiation in Lupus Nephritis",
abstract = "Activated T cells play crucial roles in the pathogenesis of autoimmune diseases, including lupus nephritis (LN). The activation of calcineurin/nuclear factor of activated T cells (NFAT) and STAT4 signaling is essential for T cells to perform various effector functions. Here, we identified the growth factor midkine (MK; gene name, Mdk) as a novel regulator in the pathogenesis of 2,6,10,14-tetramethylpentadecane-induced LN via activation of NFAT and IL-12/STAT4 signaling. Wild-type (Mdk+/+) mice showed more severe glomerular injury than MK-deficient (Mdk−/−) mice, as demonstrated by mesangial hypercellularity and matrix expansion, and glomerular capillary loops with immune-complex deposition. Compared with Mdk−/− mice, the frequency of splenic CD69+ T cells and T helper (Th) 1 cells, but not of regulatory T cells, was augmented in Mdk+/+ mice in proportion to LN disease activity, and was accompanied by skewed cytokine production. MK expression was also enhanced in activated CD4+ T cells in vivo and in vitro. MK induced activated CD4+ T cells expressing CD69 through nuclear activation of NFAT transcription and selectively increased in vitro differentiation of naive CD4+ T cells into Th1 cells by promoting IL-12/STAT4 signaling. These results suggest that MK serves an indispensable role in the NFAT-regulated activation of CD4+ T cells and Th1 cell differentiation, eventually leading to the exacerbation of LN.",
author = "Tomohiro Masuda and Kayaho Maeda and Waichi Sato and Tomoki Kosugi and Yuka Sato and Hiroshi Kojima and Noritoshi Kato and Takuji Ishimoto and Naotake Tsuboi and Kenji Uchimura and Yukio Yuzawa and Shoichi Maruyama and Kenji Kadomatsu",
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Masuda, T, Maeda, K, Sato, W, Kosugi, T, Sato, Y, Kojima, H, Kato, N, Ishimoto, T, Tsuboi, N, Uchimura, K, Yuzawa, Y, Maruyama, S & Kadomatsu, K 2017, 'Growth Factor Midkine Promotes T-Cell Activation through Nuclear Factor of Activated T Cells Signaling and Th1 Cell Differentiation in Lupus Nephritis', American Journal of Pathology, 巻. 187, 番号 4, pp. 740-751. https://doi.org/10.1016/j.ajpath.2016.12.006

Growth Factor Midkine Promotes T-Cell Activation through Nuclear Factor of Activated T Cells Signaling and Th1 Cell Differentiation in Lupus Nephritis. / Masuda, Tomohiro; Maeda, Kayaho; Sato, Waichi; Kosugi, Tomoki; Sato, Yuka; Kojima, Hiroshi; Kato, Noritoshi; Ishimoto, Takuji; Tsuboi, Naotake; Uchimura, Kenji; Yuzawa, Yukio; Maruyama, Shoichi; Kadomatsu, Kenji.

:: American Journal of Pathology, 巻 187, 番号 4, 01.04.2017, p. 740-751.

研究成果: Article

TY - JOUR

T1 - Growth Factor Midkine Promotes T-Cell Activation through Nuclear Factor of Activated T Cells Signaling and Th1 Cell Differentiation in Lupus Nephritis

AU - Masuda, Tomohiro

AU - Maeda, Kayaho

AU - Sato, Waichi

AU - Kosugi, Tomoki

AU - Sato, Yuka

AU - Kojima, Hiroshi

AU - Kato, Noritoshi

AU - Ishimoto, Takuji

AU - Tsuboi, Naotake

AU - Uchimura, Kenji

AU - Yuzawa, Yukio

AU - Maruyama, Shoichi

AU - Kadomatsu, Kenji

PY - 2017/4/1

Y1 - 2017/4/1

N2 - Activated T cells play crucial roles in the pathogenesis of autoimmune diseases, including lupus nephritis (LN). The activation of calcineurin/nuclear factor of activated T cells (NFAT) and STAT4 signaling is essential for T cells to perform various effector functions. Here, we identified the growth factor midkine (MK; gene name, Mdk) as a novel regulator in the pathogenesis of 2,6,10,14-tetramethylpentadecane-induced LN via activation of NFAT and IL-12/STAT4 signaling. Wild-type (Mdk+/+) mice showed more severe glomerular injury than MK-deficient (Mdk−/−) mice, as demonstrated by mesangial hypercellularity and matrix expansion, and glomerular capillary loops with immune-complex deposition. Compared with Mdk−/− mice, the frequency of splenic CD69+ T cells and T helper (Th) 1 cells, but not of regulatory T cells, was augmented in Mdk+/+ mice in proportion to LN disease activity, and was accompanied by skewed cytokine production. MK expression was also enhanced in activated CD4+ T cells in vivo and in vitro. MK induced activated CD4+ T cells expressing CD69 through nuclear activation of NFAT transcription and selectively increased in vitro differentiation of naive CD4+ T cells into Th1 cells by promoting IL-12/STAT4 signaling. These results suggest that MK serves an indispensable role in the NFAT-regulated activation of CD4+ T cells and Th1 cell differentiation, eventually leading to the exacerbation of LN.

AB - Activated T cells play crucial roles in the pathogenesis of autoimmune diseases, including lupus nephritis (LN). The activation of calcineurin/nuclear factor of activated T cells (NFAT) and STAT4 signaling is essential for T cells to perform various effector functions. Here, we identified the growth factor midkine (MK; gene name, Mdk) as a novel regulator in the pathogenesis of 2,6,10,14-tetramethylpentadecane-induced LN via activation of NFAT and IL-12/STAT4 signaling. Wild-type (Mdk+/+) mice showed more severe glomerular injury than MK-deficient (Mdk−/−) mice, as demonstrated by mesangial hypercellularity and matrix expansion, and glomerular capillary loops with immune-complex deposition. Compared with Mdk−/− mice, the frequency of splenic CD69+ T cells and T helper (Th) 1 cells, but not of regulatory T cells, was augmented in Mdk+/+ mice in proportion to LN disease activity, and was accompanied by skewed cytokine production. MK expression was also enhanced in activated CD4+ T cells in vivo and in vitro. MK induced activated CD4+ T cells expressing CD69 through nuclear activation of NFAT transcription and selectively increased in vitro differentiation of naive CD4+ T cells into Th1 cells by promoting IL-12/STAT4 signaling. These results suggest that MK serves an indispensable role in the NFAT-regulated activation of CD4+ T cells and Th1 cell differentiation, eventually leading to the exacerbation of LN.

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