CYCLOSPORINE-A AND HYDROXYCYCLOSPORINE (M-17) AFFECT THE SECRETORY PHENOTYPE OF HUMAN GINGIVAL FIBROBLASTS

The responsiveness of human gingival fibroblast populations to cyclosp orin A (CsA) and its principal metabolite, hydroxycyclosporine (M17), was evaluated in cell culture. Gingival fibroblasts exhibited a dose-d ependent accumulation and bell-shaped distribution of dansylated CsA. A 100-fold excess of non-labeled CsA prevented the accumulation of the fluorescent probe in the fibroblasts. Both CsA (400 ng/ml) and M17 (1 00 ng/ml) stimulated mean gingival fibroblast cell number to 23.2% and 36.7% above controls, and reduced mean collagen production by 37.7% a nd 37.4% below controls, respectively; however, neither CsA nor M17 af fected mean protein production in comparison to control cultures. Anal yses of responses to CsA and M17 by ligand-accumulating and non-accumu lating fibroblasts sorted out from the parent cultures did not provide consistent interstrain responses either by cells representing the upp er quartile of fluorescence or cells representing the bottom quartiles of fluorescence. These data demonstrate that CsA is accumulated by gi ngival fibroblasts and that CsA and M17 are potent modulators of gingi val fibroblast phenotype.