Cyclosporine A upregulates interleukin-6 gene expression in human gingiva: possible mechanism for gingival overgrowth

Cyclosporine A (CsA) is a widely used immunosuppressant for transplant patients and is also used for the treatment of a wide variety of systemic diseases with immunologic components. A prominent side effect of CsA administration is gingival overgrowth. It has been postulated that CsA alters fibroblast activity through effects on various cytokines such as the interleukins, however, as yet, data concerning the molecular mechanisms involved in connective tissue proliferation are still preliminary in nature. The purpose of this study was to evaluate interleukin-6 (IL-6) gene expression in gingival tissues of patients receiving CsA therapy and exhibiting gingival overgrowth. Radioimmunoassay (RIA) demonstrated a significant difference in tissue levels of IL-6 as mean +/- SEM. IL-6 content in CsA-stimulated tissue was 184.3 +/- 30.2 ng/mg total protein versus 23.3 +/- 6.5 ng/mg total protein in control tissue. In situ hybridization indicated that overgrown gingival tissues from patients taking CsA had a significantly higher content of IL-6 mRNA when compared to control tissues. Expressing IL-6 mRNA levels as silver grains/cell, CsA-stimulated tissue had 166.9 +/- 12.0 grains of IL-6 mRNA/cell while control tissue had 12.8 +/- 3.0 grains of IL-6 mRNA/cell. These results demonstrate that CsA therapy results in increased levels of IL-6 protein and IL-6 mRNA in overgrown human gingival tissues. This is the first report of CsA-upregulated IL-6 gene expression in vivo, and may explain in part the molecular mechanisms responsible for CsA-induced gingival overgrowth.