Cyclosporin A regulates interleukin-1beta and interleukin-6 expression in gingiva: implications for gingival overgrowth.

Abstract

Gingival overgrowth is a common side effect following the administration of cyclosporin A (CsA); however, the cellular mechanisms remain poorly understood. CsA's immunosuppressant properties involve the regulation of synthesis and cellular response to cytokines. A CsA-induced alteration in the cytokine profile within gingival tissue could provide a mechanism for gingival hyperplasia. The aim of this study was to investigate the effects of CsA on the production of 2 cytokines - interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) - by both gingival fibroblasts and peripheral blood mononuclear cells (PBMC). Cells were stimulated for 24 hours in the presence of CsA over a concentration range of 100 to 2,000 ng/ml and the resultant cytokine production determined by ELISA. In addition, levels of both cytokines within normal, inflamed, and overgrown gingival tissue were determined. CsA inhibited IL-6 production by gingival fibroblasts in a dose-dependent manner. In contrast, at a concentration of 2,000 ng/ml, CsA stimulated IL-6 production by PBMC (P <0.05). Fibroblasts derived from overgrown gingiva produced significantly higher levels of IL-6 than their normal counterparts (P <0.05). CsA inhibited IL-1beta production by PBMC over the whole concentration range (P <0.05). IL-1beta was not found in measurable quantities in any of the fibroblast cultures. Levels of IL-6 extracted from overgrown gingival tissue were significantly higher than in inflamed or normal tissue. In contrast IL-1beta levels in overgrown tissue were not statistically significantly greater than those in inflamed tissue. These results show that CsA does regulate cytokine expression in gingival tissue. This effect may play an important role in the pathogenesis of CsA-induced gingival overgrowth.