Journal
PLOS ONE
Volume 7, Issue 10, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0047668
Keywords
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Categories
Funding
- Medical Society of Goteborg
- Swedish Association against Rheumatism
- King Gustaf V:s 80-year Foundation
- Commission of European Union [HEALTH-F2-2010-261460]
- Swedish Research Council
- IngaBritt and Arne Lundberg Foundation
- Professor Nanna Swartz Foundation
- Torsten Soderberg Foundation
- AME Wolff Foundation
- Rune and Ulla Amlovs Trust
- Swedish Research Agency for Innovation Systems (VINNOVA)
- Swedish Foundation for Strategic Research
- Pharmacist Hedberg's Foundation
- Magnus Bergwall Foundation
- University of Goteborg
- Family Tholen and Kristlers Foundation
- Western Gotaland county council
- University of Goteborg (LUA/ALF)
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Survivin is known as an inhibitor of apoptosis and a positive regulator of cell division. We have recently identified survivin as a predictor of joint destruction in patients with rheumatoid arthritis (RA). Flt3 ligand (Flt3L) is expressed in the inflamed joints and has adjuvant properties in arthritis. Studies on 90 RA patients (median age 60.5 years [range, 24-87], disease duration 10.5 years [range, 0-35]) show a strong positive association between the levels of survivin and Flt3L in blood. Here, we present experimental evidence connecting survivin and Flt3L signaling. Treatment of BALB/c mice with Flt3L led to an increase of survivin in the bone marrow and in splenic dendritic cells. Flt3L changed the profile of survivin splice variants, increasing transcription of the short survivin40 in the bone marrow. Treatment with an Flt3 inhibitor reduced total survivin expression in bone marrow and in the dendritic cell population in spleen. Inhibition of survivin transcription in mice, by shRNA lentiviral constructs, reduced the gene expression of Flt3L. We conclude that expression of survivin is a downstream event of Flt3 signaling, which serves as an essential mechanism supporting survival of leukocytes during their differentiation, and maturation of dendritic cells, in RA.
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