Inhibition of neutrophil responses by cyclosporin A. An insight into molecular mechanisms

Objective. Cyclosporin A (CsA) is an effective agent in rheumatoid arthriti s (RA), slowing joint damage progression. Its therapeutic effect on T lymph ocytes has been studied extensively, but there is little information availa ble about neutrophils, the cells responsible for a substantial proportion o f inflammation. A study was performed to investigate the in vitro effects o f CsA on neutrophil functions triggered by several agonists and determine w hether the drug could counteract the binding of formyl-methionyl-leucyl-phe nylalanine (fMLP) to its receptor and or modulate changes in the intracellu lar Ca2+ concentration ([Ca2+](i)). Methods. CsA was added to neutrophils 5-50 min before the incubation steps for neutrophil function assays (chemotaxis, superoxide anion production, ly sozyme 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 agoni sts. However, it did not significantly affect either basal or agonist-stimu lated neutrophil [Ca2+](i) and the interaction between fMLP and its recepto r. Conclusions. Because of its in vitro inhibition of neutrophil functions, Cs A appears to have considerable potential as an anti-inflammatory drug. More over, as it is also a potent immunosuppressive agent, it may reduce the pro gression of joint damage in RA. More work remains to be done to clarify the molecular mechanism of CsA action on neutrophils.