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

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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.

Original languageEnglish
Pages (from-to)740-751
Number of pages12
JournalAmerican Journal of Pathology
Volume187
Issue number4
DOIs
Publication statusPublished - 01-04-2017

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All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

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, 187(4), 740-751. https://doi.org/10.1016/j.ajpath.2016.12.006