Growth factors and proliferation of cultured rat gingival cells in response to cyclosporin A.
OBJECTIVE
The prominent side-effect of cyclosporin A, an immunosuppressive drug, in oral tissues is gingival outgrowth, although the exact mechanism underlying this side-effect is unclear. The main purposes of the present study were to determine whether cyclosporin A induced the gingival outgrowth by promoting proliferation of gingival cells and whether growth factors such as transforming growth factor-betas (TGF-betas), fibroblast growth factor-2 (FGF-2), platelet-derived growth factors (PDGFs), and insulin-like growth factors (IGFs) are involved in the possible changes in the proliferation of gingival cells induced by cyclosporin A.


METHODS
Cells isolated from rat gingival tissues were cultured with cyclosporin A or IGF-I for 3 days. The effects of cyclosporin A or IGF-I on the proliferation of cultured rat gingival cells were analyzed with a CellTiter 96 proliferation assay kit. The mRNA expression levels for TGF-betas, FGF-2, PDGFs, IGFs, insulin-like growth factor receptors (IGFRs), and insulin-like growth factor binding proteins (IGFBPs) in the rat gingival cells treated with cyclosporin A were measured using competitive reverse transcription-polymerase chain reaction (RT-PCR).


RESULTS
Cyclosporin A induced 23-25% (p < 0.001) increases in the proliferation of rat gingival cells and approximately 130% (p < 0.05) and 60% (p < 0.05) elevations in the mRNA expression levels for TGF-beta1 and FGF-2, respectively. On the other hand, exogenous IGF-I induced 8-11% (p < 0.05) increases in the proliferation, but cyclosporin A induced 30-80% (p < 0.05-0.01) reductions in the mRNA expression levels for endogenous IGF-I, IGFR1, IGFBP2, IGFBP3, IGFBP5, and IGFBP6.


CONCLUSIONS
Cyclosporin A stimulates the proliferation of rat gingival cells. TGF-beta1 and FGF-2 could be involved, but IGFs, IGFRs and IGFBPs could not be directly involved in this cyclosporin A induced-stimulation of the gingival cell proliferation.
Yoshida
Takumasa
T
Department of Periodontics and Endodontics, Tsurumi University School of Dental Medicine, Yokohama, Japan.
Nagata
Junji
J
Yamane
Akira
A
D000818:Animals; D002478:Cells, Cultured; D016572:Cyclosporine / Q000009:adverse effects*; D005881:Gingiva / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005885:Gingival Hyperplasia / Q000139:chemically induced*; D006133:Growth Substances / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects*; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
D006133:Growth Substances; D007166:Immunosuppressive Agents; D007334:Insulin-Like Growth Factor I; D016572:Cyclosporine