Cyclosporine A Upregulates Interleukin‐6 Gene Expression in Human Gingiva: Possible Mechanism for Gingival Overgrowth

Abstract

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. J Periodontol 1994;65:895–903.

Involvement of apoptotic signals in cyclosporin A-induced proliferation of human gingival fibroblast

“…Furthermore, these effects of CsA on human fibroblast proliferation may vary according to individual cell strains 9) . In contrast, other previous studies have suggested that CsA increases production of extracellular matrix, collagen and interleukin-6 but simultaneously decreases proliferation of human gingival fibroblast 10,11) . Nevertheless, it is apparent that CsA increases cell proliferation of human gingival fibroblast in vitro 12) .…”

Proteomic Analysis in Cyclosporin A-Induced Overgrowth of Human Gingival Fibroblasts

“…13,14) In contrast, other reports showed that CsA has no effect on proliferation or an inhibitory effect in gingival fibroblasts. 16,23) Nevertheless, the present study showed that CsA promoted the proliferation of HGF over 0.1-10 mM in a dose-and time-dependent manner (Fig. 1).…”

“…In contrast, some studies have suggested that CsAGO involves an increase in the amount of collagen and extracellular matrix formation rather than an increase in the number of cells. 15,16) Oxidant stresses are known to induce tissue damage, cell death, and pathogenesis. In practice, free radicals such as reactive oxygen species (ROS) are involved in pathogenesis of various diseases including cancer, degenerative neuronal disease and stroke.…”

Hipertrofia gengival em transplantados renais

“…O sucesso do seu uso sistemático trouxe como conseqüência natural a extensão da indicação terapêutica para algumas das manifestações de doenças auto-imunes 3,4,5 . Entre os efeitos adversos desta medicação, alguns autores observaram o aumento do volume gengival 6,7,8 .…”