The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/3/975/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 5, March 3, 1997 975-980

Brief Definitive Reports

Presence of Cyclophilin A in Synovial Fluids of Patients with Rheumatoid Arthritis

Andreas Billich*, Gottfried Winkler*, Heinrich Aschauer*, Antal Rot*, and Peter Peichl*,{ddagger}

From the * Sandoz Research Institute, A-1235 Vienna, and {ddagger} Kaiser Franz Joseph Hospital, Department of Rheumatology, A-1100 Vienna, Austria

Cyclophilins have been suggested to act as leukocyte chemotactic factors produced in the course of inflammation. Therefore we looked for the presence of cyclophilins in the synovial fluids (SF) from patients with rheumatoid arthritis (RA). Peptidyl prolyl cis–trans isomerase activity (PPIase) was measured in SF from knee punctures of 26 patients with RA and five patients with knee osteoarthritis (OA). PPIase was detected in SF from RA patients, but not in samples from OA patients. Enzyme activity was sensitive to inhibition by cyclosporin A (IC50 = 28–50 nM). Estimated concentrations of the SF-derived cyclophilin based on the enzyme activity were in the range of 11 to 705 nM. The presence of cyclophilin in the SF showed disease correlation; its concentration correlated with the number of cells in the SF (r = 0.91, P <0.0001) and with the percentage of neutrophils in the cellular infiltrate and was higher in more acute cases of joint swelling. In immunoblots of partially purified preparations of SF from RA patients, an ~18-kD protein band reacted with polyclonal antibodies that recognize cyclophilin A and B, but not with antibodies specific for cyclophilin B. Sequencing of this protein revealed identity of the NH2-terminal amino acids with those of human cyclophilin A. The finding is unexpected since cyclophilin B rather than A is generally regarded as the secreted isoform, the presence of cyclophilin A being confined to the cytoplasm. Our data support the hypothesis that cyclophilins may contribute to the pathogenesis of inflammatory diseases, possibly by acting as cytokines. This may offer a possible explanation of the effectiveness of cyclosporin A in RA, in addition to the known immunosuppressive effects of the drug.

Address correspondence to Peter Peichl, Dept. of Rheumatology, Kaiser Franz Joseph Hospital, Kundratstrasse 3, A-1100 Vienna.

We are indebted to Dr. Mauro Zurini and Sandoz Basle, for providing us with recombinant proteins, and to Prof. G. Spik (Université de Lille, France), for the anti-cyclophilin B antibodies. We are grateful to Dr. Brigitte Rosenwirth for helpful discussions during the initial phase of this work. We thank Dr. Fritz Schmook for help with the statistical evaluation.


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