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Am J Pathol. 2017 Apr;187(4):740-751. doi: 10.1016/j.ajpath.2016.12.006. Epub 2017 Feb 7.

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

Author information

1
Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
2
Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
3
Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: kosugi@med.nagoya-u.ac.jp.
4
Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
5
Department of Nephrology, Fujita Health University School of Medicine, Toyoake, Japan.

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.

PMID:
28183532
DOI:
10.1016/j.ajpath.2016.12.006
[Indexed for MEDLINE]

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