Regulation of gingival fibroblast interleukin-6 secretion by cyclosporine A

Background: Cyclosporine A (CsA) is a widely used immunosuppressant, with clinical applications ranging from organ transplants to chronic inflammatory diseases. One of the side effects associated with CsA treatment is the development of gingival overgrowth. Exuberant growth of connective tissue within the periodontium can result from hyperactivity of resident fibroblasts. Fibroblasts are capable of secreting interleukin-6 (IL-6), which has been shown to enhance proliferation as well as collagen and glycosaminoglycan synthesis by these cells. We tested the hypothesis that one of the pathogenetic mechanisms underlying CsA-induced fibrosis is an enhanced IL-6 secretion by gingival fibroblasts (GF) in response to this drug. Methods: The ability of CsA to upregulate GF IL-6 secretion alone or in combination with bacterial challenge or other inflammatory cytokines was tested in an in vitro system. Fibroblast cultures were established from systemically healthy gingival tissue donors and were challenged with CsA in the absence or presence of bacteria, IL-1 beta, or tumor necrosis factor (TNF) alpha as co-stimulants. Nifedipine and phenytoin were also tested to further support findings with CsA. After 72 hours of incubation, culture supernatants were collected and analyzed for IL-6 content by ELISA. Results: We have shown that GF respond to CsA with an increase in IL-6 secretion. The magnitude of this response varies among cultures derived from different tissue donors. We have also demonstrated that GF IL-6 responses to bacterial challenge or TNF alpha are downregulated by CsA. However, CsA synergizes with IL-1 beta to further upregulate IL-6 secretion, and this effect is shared by phenytoin and nifedipine. Conclusions: We conclude that one of the pathogenetic mechanisms underlying drug-induced gingival overgrowth may be enhanced secretion of IL-6 by GF in response to these medications. This is the first report on direct and indirect effects of gingival overgrowth-related medications on GF IL-6 metabolism. This work will lay the foundation for future studies directed towards the development of prevention or treatment modalities for gingival overgrowth based on blocking the fibrogenic activities of IL-6 at the cellular level.