Cyclosporin A Induces Proliferation in Human Gingival Fibroblasts via Induction of Transforming Growth Factor‐β1

Background: Cyclosporin A (CsA) is a widely used immunosuppressant that causes significant side effects including gingival overgrowth. The pathogenesis of this condition is not fully understood; however, recent studies show that CsA regulates the transcription of several cytokines including transforming growth factor‐beta 1 (TGF‐β1). In this study, we evaluated the effects of CsA and TGF‐β1 on human normal gingival (NG) fibroblast proliferation, and explored a possible autocrine stimulation of TGF‐β1 as a cellular regulator of proliferation induced by CsA in NG fibroblasts. Methods: NG fibroblast cell lines were incubated with increasing concentrations of CsA or TGF‐β1 and the proliferation index determined by automatic cell counting, BrdU incorporation, PCNA expression, and mitotic potential. To determine the effect of TGF‐β1 on the proliferation rate of NG fibroblasts under CsA treatment, NG fibroblast cultures were simultaneously treated with CsA and antisense oligonucleotides against the translation‐start site of the TGF‐β1 mRNA. Results: Treatment of NG fibroblasts with CsA or TGF‐β1 significantly stimulated the cell proliferation in a dose‐dependent manner. Furthermore, neutralization of TGF‐β1 production in CsA‐treated NG fibroblasts inhibited CsA's effect on NG fibroblast proliferation, demonstrating an autocrine stimulatory effect of TGF‐β1 in CsA‐treated NG fibroblast proliferation. Conclusion: The results presented here suggest that CsA stimulatory induction of NG fibroblast proliferation is mediated via TGF‐β1 in an autocrine fashion. J Periodontol 2003;74:1625‐1633 .