Delayed neutrophil apoptosis induced by synovial fluid in rheumatoid arthritis: role of cytokines, estrogens, and adenosine.
The fate of neutrophils at sites of inflammation, where these cells are likely exposed to both anti- and proapoptotic influences, needs to be clarified. To investigate this issue, we studied the survival of neutrophils in the presence of articular fluids from RA joints before and after immune complex activation. Eight of eleven samples of RA synovial fluid studied were found to inhibit spontaneous and immune complex-stimulated neutrophil apoptosis. No relationships were found between GM-CSF and TNF-alpha concentrations measured on each sample of synovial fluid studied and the levels of neutrophil apoptosis detectable in the presence of the same synovial fluid. Furthermore, no activity on neutrophil survival was observed at either physiologic or pharmacologic concentrations of estradiol. On the contrary, the synovial fluid anti-apoptotic activity correlates (r(2) = 0.8818, p < 0.0001) with the adenosine detected at concentrations in each sample ranging from 18.7 to 52.4 microM. Finally, synovial fluids were incapable of interfering with neutrophil activation evaluated as superoxide anion production. Our results suggest that the microenvironment of rheumatoid synovial fluid is a proinflammatory milieu responsible for the in loco persistence of activated and long-surviving neutrophils.
Division of Internal Medicine, Department of Internal Medicine and Medical Specialities, University of Genova, I-16132 Genova, Italy. otto@unige.it
Luciano
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Ottonello
Guido
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Frumento
Nicoletta
N
Arduino
Maria
M
Bertolotto
Marina
M
Mancini
Enzo
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Sottofattori
Franco
F
Dallegri
Maurizio
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Cutolo
D000241:Adenosine / Q000494:pharmacology / Q000502:physiology*; D000243:Adenosine Deaminase / Q000378:metabolism / Q000494:pharmacology; D000936:Antigen-Antibody Complex / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000494:pharmacology / Q000502:physiology*; D003864:Depression, Chemical; D004958:Estradiol / Q000032:analysis / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology / Q000502:physiology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000032:analysis; D006801:Humans; D007378:Interleukins / Q000032:analysis; D007719:Knee Joint; D009504:Neutrophils / Q000187:drug effects* / Q000473:pathology; D018384:Oxidative Stress; D016897:Respiratory Burst / Q000187:drug effects*; D013481:Superoxides / Q000378:metabolism; D013582:Synovial Fluid / Q000737:chemistry / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D000936:Antigen-Antibody Complex; D016207:Cytokines; D004967:Estrogens; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D004958:Estradiol; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000243:Adenosine Deaminase; D000241:Adenosine