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Rheumatology Advance Access published online on September 14, 2004
Rheumatology, doi:10.1093/rheumatology/keh406
Rheumatology © British Society for Rheumatology 2004; all rights reserved
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Received March 25, 2004
Accepted August 10, 2004

Original Papers

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

R. Pullerits 1*, M. Bokarewa 1, I.-M. Jonsson 1, M. Verdrengh 1, and A. Tarkowski 1

1 Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, University of Göteborg, Sweden

* To whom correspondence should be addressed. E-mail: rille.pullerits{at}rheuma.gu.se.


  Abstract

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-{kappa}B 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-{kappa}B 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-{kappa}B 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.

Keywords: Cytochrome c; Arthritis; Inflammation; NF-{kappa}B; Cytokine; Chemokine.
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