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Activation of Fms-like tyrosine kinase 3 signaling enhances survivin expression in a mouse model of rheumatoid arthritis.
- Source :
-
PloS one [PLoS One] 2012; Vol. 7 (10), pp. e47668. Date of Electronic Publication: 2012 Oct 17. - Publication Year :
- 2012
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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.
- Subjects :
- Adult
Aged
Aged, 80 and over
Alternative Splicing drug effects
Alternative Splicing genetics
Animals
Arthritis, Rheumatoid pathology
Bone Marrow drug effects
Bone Marrow metabolism
Disease Models, Animal
Down-Regulation drug effects
Enzyme Activation drug effects
Female
Humans
Inhibitor of Apoptosis Proteins genetics
Male
Membrane Proteins pharmacology
Mice
Mice, Inbred BALB C
Middle Aged
RNA, Small Interfering metabolism
Repressor Proteins genetics
Spleen drug effects
Spleen metabolism
Survivin
Up-Regulation drug effects
Young Adult
fms-Like Tyrosine Kinase 3 antagonists & inhibitors
Arthritis, Rheumatoid enzymology
Inhibitor of Apoptosis Proteins metabolism
Repressor Proteins metabolism
Signal Transduction drug effects
fms-Like Tyrosine Kinase 3 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 7
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 23082191
- Full Text :
- https://doi.org/10.1371/journal.pone.0047668