Inhibition of neutrophil responses by cyclosporin A. An insight into molecular mechanisms.
OBJECTIVE
Cyclosporin A (CsA) is an effective agent in rheumatoid arthritis (RA), slowing joint damage progression. Its therapeutic effect on T lymphocytes has been studied extensively, but there is little information available about neutrophils, the cells responsible for a substantial proportion of inflammation. A study was performed to investigate the in vitro effects of CsA on neutrophil functions triggered by several agonists and determine whether the drug could counteract the binding of formyl-methionyl-leucyl-phenylalanine (fMLP) to its receptor and/or modulate changes in the intracellular Ca(2+) concentration ([Ca(2+)]i).


METHODS
CsA was added to neutrophils 5-50 min before the incubation steps for neutrophil function assays (chemotaxis, superoxide anion production, lysozyme release), calcium measurements and receptor binding experiments.


RESULTS
CsA appeared to be particularly effective in lowering chemotaxis, superoxide anion production and lysozyme release induced by different agonists. However, it did not significantly affect either basal or agonist-stimulated neutrophil [Ca(2+)]i and the interaction between fMLP and its receptor.


CONCLUSIONS
Because of its in vitro inhibition of neutrophil functions, CsA appears to have considerable potential as an anti-inflammatory drug. Moreover, as it is also a potent immunosuppressive agent, it may reduce the progression of joint damage in RA. More work remains to be done to clarify the molecular mechanism of CsA action on neutrophils.
Spisani
S
S
Department of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, Italy.
Fabbri
E
E
Muccinelli
M
M
Cariani
A
A
Barbin
L
L
Trotta
F
F
Dovigo
L
L
D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D002364:Caseins / Q000494:pharmacology; D015550:Cell Degranulation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000037:antagonists & inhibitors; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018000:Receptors, Peptide / Q000378:metabolism; D016897:Respiratory Burst / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015054:Zymosan / Q000494:pharmacology
D002364:Caseins; D018000:Receptors, Peptide; D013481:Superoxides; D009240:N-Formylmethionine Leucyl-Phenylalanine; D016572:Cyclosporine; D015054:Zymosan; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium