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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Arthritis+Res+Ther
2017 ; 19
(1
): 137
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Leucine-rich alpha 2 glycoprotein promotes Th17 differentiation and
collagen-induced arthritis in mice through enhancement of TGF-?-Smad2 signaling
in naïve helper T cells
#MMPMID28615031
Urushima H
; Fujimoto M
; Mishima T
; Ohkawara T
; Honda H
; Lee H
; Kawahata H
; Serada S
; Naka T
Arthritis Res Ther
2017[Jun]; 19
(1
): 137
PMID28615031
show ga
BACKGROUND: Leucine-rich alpha 2 glycoprotein (LRG) has been identified as a
serum protein elevated in patients with active rheumatoid arthritis (RA).
Although the function of LRG is ill-defined, LRG binds with transforming growth
factor (TGF)-? and enhances Smad2 phosphorylation. Considering that the imbalance
between T helper 17 (Th17) cells and regulatory T cells (Treg) plays important
roles in the pathogenesis of RA, LRG may affect arthritic pathology by enhancing
the TGF-?-Smad2 pathway that is pivotal for both Treg and Th17 differentiation.
The purpose of this study was to explore the contribution of LRG to the
pathogenesis of arthritis, with a focus on the role of LRG in T cell
differentiation. METHODS: The differentiation of CD4 T cells and the development
of collagen-induced arthritis (CIA) were examined in wild-type mice and LRG
knockout (KO) mice. To examine the influence of LRG on T cell differentiation,
naïve CD4 T cells were isolated from LRG KO mice and cultured under Treg- or
Th17-polarization condition in the absence or presence of recombinant LRG.
RESULTS: In the CIA model, LRG deficiency led to ameliorated arthritis and
reduced Th17 differentiation with no influence on Treg differentiation. By
addition of recombinant LRG, the expression of IL-6 receptor (IL-6R) was enhanced
through TGF-?-Smad2 signaling. In LRG KO mice, the IL-6R expression and
IL-6-STAT3 signaling was attenuated in naïve CD4 T cells, compared to wild-type
mice. CONCLUSIONS: Our findings suggest that LRG upregulates IL-6R expression in
naïve CD4 T cells by the enhancement of TGF-?-smad2 pathway and promote Th17
differentiation and arthritis development.