We have shown previously that a calcium-binding protein complex, calprotectin, derived from polymorphonuclear leukocytes exerts a cytostatic and cytolytic effect against a very broad range of tumor cell lines. We also described that calprotectin is an apoptosis-inducing factor for certain tumor cells and that zinc ion attenuates the calprotectin activities. The titers of the factor in body fluids are known to increase greatly in various types of inflammation. In this study, to learn the role of calprotectin in inflammation, the growth-inhibitory and the apoptosis-inducing activities of the factor against normal fibroblasts were examined because fibroblasts are a cell type constituting a local inflammatory site. Rat calprotectin inhibited the growth of murine embryonic as well as human dermal fibroblasts. Although calprotectin induced apoptotic morphology in both fibroblasts, the reaction was slower and less efficient than cases using tumor cells as targets. The activities were significantly abrogated by 10-50 microM Zn2+, Cu2+, Mn2+, or Fe2+, respectively, whereas the trivalent cations Al3+ and Fe3+ had no effect. The dose-response curves of the calprotectin effects were shifted to about 10-fold lower concentration ranges in the divalent metal ion-depleted medium. These results suggest that calprotectin extracellularly affects the inflammatory processes by modulating the growth and survival states of normal fibroblasts, and that the effects are physiologically controlled by several metal ions.