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Rheumatology 2002; 41: 1249-1260
© 2002 British Society for Rheumatology

Original Papers

Synovial fluid from patients with rheumatoid arthritis inhibits neutrophil apoptosis: role of adenosine and proinflammatory cytokines

L. Ottonello, M. Cutolo1,, G. Frumento2, N. Arduino3, M. Bertolotto3, M. Mancini, E. Sottofattori3 and F. Dallegri

Division of Internal Medicine and
1 Division of Rheumatology, Department of Internal Medicine and Medical Specialties, University of Genova
2 Immunogenetics Department, National Institute of Cancer Research and
3 Department of Pharmaceutical Sciences, University of Genova, Genova, Italy

Objective. In synovial fluid (SF) from patients with rheumatoid arthritis (RA), neutrophils are exposed to proinflammatory mediators endowed with either anti-apoptotic or pro-apoptotic properties. We investigated neutrophil apoptosis in the presence of SF from 11 RA patients.

Methods. SF was obtained from affected knees of 11 patients with RA. Human neutrophil apoptosis was evaluated by light microscopic examination and flow-cytometric analysis of annexin V binding. Immune complex-induced neutrophil activation was evaluated as superoxide anion production. Adenosine levels in SF were detected by chromatographic analysis and cytokine levels were studied by enzyme-linked immunosorbent assay.

Results. Spontaneous and immune complex-triggered neutrophil apoptosis was reduced by SF from eight out of 11 patients. Immune complex-induced neutrophil activation was unaffected by SF. The cytokines tested had no role in promoting the anti-apoptotic activity of SF. On the contrary, the anti-apoptotic activity of SF was found to depend on the presence of adenosine. Adenosine levels detected in the various samples of SF correlated significantly with the anti-apoptotic activity of the fluids and with the number of apoptotic neutrophils detected in the articular exudate.

Conclusion. The microenvironment of rheumatoid SF is a proinflammatory milieu responsible for the in loco persistence of activated and long-surviving neutrophils. Adenosine plays a crucial role in this phenomenon, which is related to anti-apoptotic activity.

KEY WORDS: Neutrophils, Rheumatoid arthritis, Apoptosis, Adenosine, GM-CSF, TNF-{alpha}.

Correspondence to: M. Cutolo, Dipartimento di Medicina Interna e Specialità Mediche, Viale Benedetto XV n.6, I-16132 Genova, Italy.


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