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THU0008 Leucine-Rich Alpha 2 Glycoprotein Promotes The Differentiation of Th17 and Deteriorates Collagen Induced Arthritis through Enhancement of TGF Beta Signaling
  1. H. Urushima,
  2. M. Fujimoto,
  3. T. Mishima,
  4. T. Ohkawara,
  5. H. Honda,
  6. S. Serada,
  7. T. Naka
  1. National Institute of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan

Abstract

Background We have identified leucine-rich alpha 2 glycoprotein (LRG) as a disease marker of rheumatoid arthritis (RA) 1). Although LRG is produced in site of inflammation such as synovial tissues, its function is still unclear. Recently, LRG is reported to bind with TGF-β and enhance of Smad2 phosphorylation 2). TGF-β is essential for differentiation of Th17. Th17 plays important roles in the pathogenesis of RA, for example, by regulating osteoclast differentiation. In collagen induced arthritis (CIA), a mouse model of RA, phosphorylation of Smad2 in CD4 T cells is important for the Th17 differentiation and the induction of arthritis 3). Thus, LRG may be involved in the pathogenesis of RA through the regulation of T lymphocyte differentiation.

Objectives In this study, we aimed to elucidate the function of LRG on T lymphocyte differentiation and to examine the involvement of LRG in the pathogenesis of RA.

Methods Naïve T lymphocyte were isolated from WT or LRG KO mice to examine the effects of LRG on the differentiation into Th17 and Treg in the absence or presence of recombinant LRG. Male C57BL/6 mice and LRG KO mice were subjected to collagen-induced arthritis (CIA).

Results In the presence of TGF-β alone, the differentiation of Treg was promoted by LRG. However, in the presence both TGF-β and IL6, LRG enhanced the differentiation into Th17 by increasing both Smad2 and STAT3 phosphorylation. The phosphorylation of p38 was also increased by LRG. In addition, the expression of IL6 receptor in naïve T cells was significantly lower in LRG KO mice than in WT mice. In CIA model, arthritis score was significantly lower in LRG KO mice than in control group. The numbers of Th17 in regional lymph nodes and serum levels of IL17 were significantly lower in LRG KO mice than in WT mice.

Conclusions LRG promoted TGF-β-induced Smad2 phosphorylation under Th17 differentiation condition. Since Smad2 signal increases the expression of IL6 receptor in naïve T cells 4), LRG might increase the expression of IL6 receptor through Smad2 signal, leading to enhanced the phosphorylation of STAT3 which is an essential transcription factor in the differentiation of Th17 4)5). LRG also enhanced phosphorylation of p38 MAPK which is involved in the proliferation of helper T cells. In addition, recent study reported that p38 MAPK plays an important role in the production of IL17 6)7)

Taken together, our study suggested that LRG promotes both the proliferation and Th17 differentiation of naive T cells under inflammatory state, leading to deterioration of arthritis.

  1. Ann Rheum Dis 2010

  2. Oncotarget 2015

  3. Nat Commun 2015

  4. J Biol Chem 2010

  5. Nat Commun 2015

  6. J Immunol 2010

  7. Blood 2011

Disclosure of Interest None declared

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