Extracellular cytochrome c, a mitochondrial apoptosis-related protein, induces arthritis

• OBJECTIVES: The aim of the study was to assess the role of extracellular cytochrome c as an inducer of joint inflammation and to examine its levels in sera and synovial fluids of rheumatoid arthritis (RA) patients. METHODS: Mice were injected intra-articularly with different doses of cytochrome c and joints were evaluated histopathologically and immunohistochemically 3 and 10 days later. In addition, mouse spleen cells were stimulated with different concentrations of cytochrome c, followed by assessment of NF-kappaB activation and cytokine production. Sera and synovial fluid from RA patients and sera from healthy individuals were assessed with respect to cytochrome c levels by an enzyme-linked immunoassay technique. RESULTS: Histopathological signs of arthritis were evident in 75% of animals following intra-articular injection of cytochrome c. Synovitis was characterized by influx of Mac-1+ cells. In vivo depletion of neutrophils and monocytes led to abrogation of arthritis. Stimulation of mouse spleen cells in vitro with cytochrome c resulted in activation of NF-kappaB and release of proinflammatory cytokines and chemokines. Cytochrome c levels in RA patients' sera were significantly lower than in healthy controls. Further, cytochrome c levels in synovial fluid were significantly lower than in corresponding blood samples. CONCLUSIONS: Our findings demonstrate that extracellular cytochrome c displays direct proinflammatory properties mediated by activation of NF-kappaB and causing neutrophil and monocyte triggered inflammation. We hypothesize that decreased levels of cytochrome c in RA patients reflect consumption of this molecule in the synovial tissue, decreasing apoptosis and shifting the balance towards inflammation.

Nyckelord

Adult

Aged

Animals

*Apoptosis

Arthritis

Experimental/*chemically induced/pathology

Arthritis

Rheumatoid/*metabolism

Cells

Cultured

Chemokines/biosynthesis

Cytochromes c/analysis/pharmacology/*toxicity

Electrophoretic Mobility Shift Assay

Extracellular Fluid/metabolism

Female

Humans

Injections

Intra-Articular

Mice

Mice

Inbred BALB C

Middle Aged

NF-kappa B/metabolism

Neutrophils/physiology

Spleen/cytology/drug effects/immunology

Synovial Fluid/chemistry

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)