INTERLEUKIN-1-BETA-INDEPENDENT AND TUMOR NECROSIS FACTOR-ALPHA-INDEPENDENT MONOCYTE STIMULATION OF FIBROBLAST COLLAGENASE ACTIVITY

To investigate the mechanism of cyclosporine (Cs)‐induced fibrous gingival enlargement, the indirect effects of Cs on fibroblast collagenolysis via the drug's effect on the synthesis of the fibroblast regulatory monokines interleukin‐1β (IL‐1β) and tumor necrosis factor‐α (TNFα) have been studied. Peripheral blood monocytes stimulated with lipopolysaccharide (LPS) for 48 h produced conditioned media (MCM‐LPS) that contained 665 pg/ml IL‐1β and 16 pg/ml TNFα and significantly (P < 0.001) enhanced the collagenase activity of a fibroblast strain (GN 23) derived from a healthy individual with clinically normal gingiva. The concurrent addition of Cs (50, 100, or 150 ng/ml) with LPS to the monocytes (MCM‐LPS‐Cs) significantly diminished their ability to enhance GN 23 collagenase activity in a dose‐dependent manner, with MCM‐LPS‐Cs (150 ng/ml) causing the greatest effect. Cs also significantly inhibited IL‐1β and TNFα production. Although the greatest inhibition of both cytokines was at 50 ng/ml Cs, the corresponding MCM‐LPS‐Cs caused the least diminution (16%) of the collagenase stimulation caused by MCM‐LPS (no Cs). This suggested that factor(s) other than or in addition to IL‐1β and TNFα might be responsible for the stimulation of GN 23 collagenase activity. MCM‐LPS depleted of IL‐1β by affinity chromatography retained its stimulatory effect on GN 23 collagenolysis, and human recombinant IL‐1β and TNFα, when tested alone or together at levels found in the stimulatory MCM‐LPS and MCM‐LPS‐Cs, did not stimulate GN 23 collagenase activity as did the crude conditioned media. This evidence suggested that the conditioned media contained the complex mixture of cytokines necessary to stimulate collagenase activity of this fibroblast strain and that IL‐1β and TNFα were not necessarily involved. Cs may alter the synthesis of other collagenase‐stimulating cytokines, accounting for the diminished ability of Cs‐treated monocytes to enhance collagenase activity of susceptible fibroblast strains. Decreased collagenase activity, therefore, resulting from Cs suppression of monokine production, may be an important factor in the development of fibrous gingival enlargement seen in some susceptible patients treated with Cs. Copyright © 1990 Wiley‐Liss, Inc.