Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Aged, 80 and over
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Alternative Splicing / drug effects
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Alternative Splicing / genetics
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Animals
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Arthritis, Rheumatoid / enzymology*
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Arthritis, Rheumatoid / pathology
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Bone Marrow / drug effects
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Bone Marrow / metabolism
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Disease Models, Animal
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Down-Regulation / drug effects
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Enzyme Activation / drug effects
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Female
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Humans
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Inhibitor of Apoptosis Proteins / genetics
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Inhibitor of Apoptosis Proteins / metabolism*
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Male
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Membrane Proteins / pharmacology
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Mice
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Mice, Inbred BALB C
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Middle Aged
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RNA, Small Interfering / metabolism
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Signal Transduction* / drug effects
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Spleen / drug effects
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Spleen / metabolism
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Survivin
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Up-Regulation / drug effects
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Young Adult
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fms-Like Tyrosine Kinase 3 / antagonists & inhibitors
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fms-Like Tyrosine Kinase 3 / metabolism*
Substances
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BIRC5 protein, human
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Birc5 protein, mouse
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Inhibitor of Apoptosis Proteins
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Membrane Proteins
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RNA, Small Interfering
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Repressor Proteins
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Survivin
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flt3 ligand protein
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Flt3 protein, mouse
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fms-Like Tyrosine Kinase 3
Grants and funding
This work was funded by grants from the Medical Society of Göteborg, the Swedish Association against Rheumatism, the King Gustaf V:s 80-year Foundation, the Commission of European Union (HEALTH-F2-2010-261460), the Swedish Research Council, IngaBritt and Arne Lundberg Foundation, Professor Nanna Swartz Foundation, Torsten Söderberg Foundation, AME Wolff Foundation, Rune and Ulla Amlövs Trust, the Swedish Research Agency for Innovation Systems (VINNOVA), the Swedish Foundation for Strategic Research, the Pharmacist Hedberg’s Foundation, Magnus Bergwall Foundation, the University of Göteborg, the Family Thölen and Kristlers Foundation, the Regional agreement on medical training and clinical research between the Western Götaland county council and the University of Göteborg (LUA/ALF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.