| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Outline of Final Research Achievements |
Discovery of the mechanism of active demethylation by TET proteins has rapidly advanced understanding of DNA methylation dynamism. Here, we demonstrate that TET3 is induced by inflammatory cytokine stimulation, and plays an important role in joint destruction in rheumatoid arthritis (RA). Arthritis was induced in C57BL/6 wild type and TET3 heterozygous-deficient (TET3+/-) mice with K/BxN serum. The arthritis score and bone erosion score were significantly decreased in the TET3+/- mice. In RA patient-derived fibroblast-like synoviocytes (FLS), the TET3 expression and 5-hydroxymethylcytosine levels were significantly increased by TNF stimulation. In addition, TET3 knockdown inhibited the TNF-induced production of CCL2 and ICAM-1 in RA FLS. These results suggest that continuous exposure to inflammatory cytokines results in leaving an inflammatory memory in FLS in a TET3-dependent manner, thereby promoting pannus formation and increasing the probability of joint destruction.
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