Cyclosporin A Regulates Interleukin‐1ßand Interleukin‐6 Expression in Gingiva: Implications for Gingival Overgrowth

Abstract

Background: 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‐1ß(IL‐1ß) and interleukin‐6 (IL‐6) — by both gingival fibroblasts and peripheral blood mononuclear cells (PBMC). Methods: 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. Results: 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‐1ßproduction by PBMC over the whole concentration range ( P <0.05). IL‐1ßwas 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‐1ßlevels in overgrown tissue were not statistically significantly greater than those in inflamed tissue. Conclusions: 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. J Periodontol 1999;70:294‐300.

Effect of Transforming Growth Factor‐β1, Interleukin‐6, and Interferon‐γ on the Expression of Type I Collagen, Heat Shock Protein 47, Matrix Metalloproteinase (MMP)‐1 and MMP‐2 by Fibroblasts from Normal Gingiva and Hereditary Gingival Fibromatosis

“…22,23,[52][53][54] TGF-β1 and IL-6 are recognized as key mediators responsible for the accumulation of extracellular matrix in both drug-induced gingival overgrowth and HGF. 7,25,[55][56][57][58][59] It has been observed that, in vitro, TGF-β1 and IL-6 upregulate collagens, fibronectins, and laminins in a variety of cell types. 60 However, increased synthesis does not necessarily lead to extracellular matrix accumulation.…”

Expression of Matrix Metalloproteinases in Cyclosporin‐Treated Gingival Fibroblasts Is Regulated by Transforming Growth Factor (TGF)‐β1 Autocrine Stimulation

“…It has been demonstrated that CsA affects gingival fibroblast proliferation, 38 promotes abnormal synthesis of collagen and other extracellular matrix molecules, 39 decreases collagen turnover by inhibiting collagen phagocytosis and collagen degrading enzymes, 40,41 and also appears to act on abnormal cytokine production. 42,43 Although the exact mechanism by which CsA induces gingival overgrowth remains unclear, our understanding of the biochemical mechanisms involved in producing these tissue alterations is evolving. For example, increased TGF-β1 production has recently been demonstrated in CsAinduced gingival overgrowth 44 as well as in other fibrotic side effects of CsA-treatment.…”

Drug-induced gingival hyperplasia: a retrospective study using spontaneous reporting system databases

“…Some hypotheses have suggested the role of factors such as 1) fibroblasts [27–32], 2) inflammatory cytokines [30, 33–36], and 3) matrix metalloproteinase (MMP) synthesis [31]. CsA, nifedipine, and phenytoin promote the modeling of periodontal fibroblasts through the synthesis of gingival fibroblasts or inhibition of the decomposition of gingival fibroblasts [27–31].…”