Reply

L. Ottonello, M. Cutolo, G. Frumento1, N. Arduino2, M. Bertolotto, M. Mancini, E. Sottofattori2 and F. Dallegri

Internal Medicine and Medical Specialties, University of Genova Medical School, 1Immunogenetics, National Institute of Cancer Research and 2Pharmaceutical Sciences, University of Genova, Genova, Italy

Correspondence to: F. Dallegri, Department of Internal Medicine, DIMI-Viale Benedetto XV, n6, I-16132, Genova, Italy. E-mail: dalle{at}unige.it

We fully agree with the remarks of Dr Bell and colleagues about the role of neutrophil apoptosis in the persistence and resolution of the inflammatory reaction. In particular, we concur with the concept of neutrophil apoptosis at sites of inflammation as a dynamic process modulated by opposite signals detectable in synovial fluids, either pro-apoptotic or anti-apoptotic [13]. Thus, it is conceivable that the differences observed between our studies [4, 5] may well reflect differences in the activity and/or phase of the disease and possibly the individual genetic pattern.

The fate of neutrophils at sites in the inflamed joint is also modulated by pro- and anti-apoptotic influences during the phase of cell recruitment, i.e. ß2-integrin and selectin cross-linking during endothelial transmigration, and chemokine stimulation [3, 6, 7]. Thus, comparisons between the rates of apoptosis of neutrophils from the peripheral blood and synovial fluid may also reflect these factors, as well as the different age of circulating vs migrated cells. Although we did not provide data about this issue in our study, our observations are strengthened by the strict inverse correlation between the anti-apoptotic activity of synovial fluid and the number of neutrophils with morphological features of apoptosis in the same fluid.

Our data are in agreement with reports showing that biological fluids from pathologies characterized by neutrophilic inflammation have neutrophil anti-apoptotic properties. However, in order to clarify the points mentioned above there is a need for thorough investigation of the issue of neutrophil apoptosis in the resolution or perpetuation of the inflammatory response and the question of what local factors might influence these mechanisms.

References

  1. Ottonello L, Frumento G, Arduino N, Dapino P, Tortolina G, Dallegri F. Immune complex stimulation of neutrophil apoptosis: investigating the involvement of oxidative and nonoxidative pathways. Free Rad Biol Med 2001;30:161–9[CrossRef][ISI][Medline]
  2. Hashimoto H, Tanaka M, Suda T et al. Soluble Fas ligand in the joints of patients with rheumatoid arthritis and osteoarthritis. Arthritis Rheum 1998,41:657[CrossRef][ISI][Medline]
  3. Colotta F, Re F, Polentarutti N, Sozzani S, Mantovani A. Modulation of granulocyte survival and programmed cell death by cytokines and bacterial products. Blood 1992;80:2012–20[Abstract]
  4. Bell AL, Magill MK, McKane R, Irvine AE. Human blood and synovial fluid neutrophils cultured in vitro undergo programmed cell death which is promoted by addition of synovial fluid. Ann Rheum Dis 1995;54:910–5[Abstract]
  5. Ottonello L, Cutolo M, Frumento G et al. Synovial fluid from patients with rheumatoid arthritis inhibits neutrophil apoptosis: role of adenosine and proinflammatory cytokines. Rheumatology 2002;41:1241–60
  6. Walzog B, Jeblonski F, Zakrzewicz A, Gaehtgens P. Beta2 integrins (CD11/CD18) promote apoptosis of human neutrophils. FASEB J 1997;11:1177–86[Abstract/Free Full Text]
  7. Watson RW, Rotstein OD, Nathens AB, Parodo J, Marshall JC. Neutrophil apoptosis is modulated by endothelial transmigration and adhesion molecule engagement. J Immunol 1997;158:945–53[Abstract]
Accepted 25 February 2003





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