Growth Factor Midkine Promotes T-Cell Activation through Nuclear Factor of Activated T Cells Signaling and Th1 Cell Differentiation in Lupus Nephritis.
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.
Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Tomohiro
T
Masuda
Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Kayaho
K
Maeda
Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Waichi
W
Sato
Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: kosugi@med.nagoya-u.ac.jp.
Tomoki
T
Kosugi
Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Yuka
Y
Sato
Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Hiroshi
H
Kojima
Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Noritoshi
N
Kato
Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Takuji
T
Ishimoto
Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Naotake
N
Tsuboi
Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Kenji
K
Uchimura
Department of Nephrology, Fujita Health University School of Medicine, Toyoake, Japan.
Yukio
Y
Yuzawa
Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Shoichi
S
Maruyama
Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Kenji
K
Kadomatsu
D000818:Animals; D002454:Cell Differentiation; D016207:Cytokines / Q000172:deficiency / Q000378:metabolism*; D007249:Inflammation / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000293:injuries / Q000473:pathology / Q000648:ultrastructure; D008181:Lupus Nephritis / Q000276:immunology / Q000473:pathology*; D008213:Lymphocyte Activation; D051379:Mice; D000078792:Midkine; D008954:Models, Biological; D050778:NFATC Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction; D013154:Spleen / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology*
D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D050778:NFATC Transcription Factors; D000078792:Midkine