Activation of Fms-like tyrosine kinase 3 signaling enhances survivin expression in a mouse model of rheumatoid arthritis.

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Immunology in the medical area (hsv//eng)

Nyckelord

Adult

Aged

Aged

80 and over

Alternative Splicing

drug effects

genetics

Animals

Arthritis

Rheumatoid

enzymology

pathology

Bone Marrow

drug effects

metabolism

Disease Models

Animal

Down-Regulation

drug effects

Enzyme Activation

drug effects

Female

Humans

Inhibitor of Apoptosis Proteins

genetics

metabolism

Male

Membrane Proteins

pharmacology

Mice

Mice

Inbred BALB C

Middle Aged

RNA

Small Interfering

metabolism

Repressor Proteins

genetics

metabolism

Signal Transduction

drug effects

Spleen

drug effects

metabolism

Up-Regulation

drug effects

Young Adult

fms-Like Tyrosine Kinase 3

antagonists & inhibitors

metabolism

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)