The up-regulation of type I plasminogen activator inhibitor in human gingival fibroblasts stimulated with cyclosporin A.
OBJECTIVE
Cyclosporin A is used as an immunosuppressive agent and its prominent side-effect is the induction of fibrous gingival overgrowth. The progression of fibrous gingival overgrowth results from the accumulation of extracellular matrix. Type I plasminogen activator inhibitor (PAI-1) acts as the inhibitor of extracellular matrix degradation and is involved in some fibrotic diseases. However, little is known about the correlation between PAI-1 and cyclosporin A-induced gingival overgrowth. The aim of this study was to investigate the effects of cyclosporin A on the expression of PAI-1 mRNA and protein in human gingival fibroblasts human gingival fibroblasts in vitro and to compare PAI-1 expression in normal healthy gingival tissues and cyclosporin A-induced gingival overgrowth specimens in vivo.


METHODS
Quantitative reverse transcription-polymerase chain reaction and western blot assay were used to investigate the effects on human gingival fibroblasts exposed to cyclosporin A. In addition, 10 cyclosporin A-induced gingival overgrowth specimens and five normal gingival tissues were examined by immunohistochemistry.


RESULTS
Investigations of the time dependence of PAI-1 mRNA expression in human gingival fibroblasts treated with 200 ng/ml of cyclosporin A revealed a rapid accumulation of the transcript: a significant signal was first detectable after 1 h of exposure and the signal remained elevated throughout the 24-h incubation period (p < 0.05). Cyclosporin A was also found to up-regulate PAI-1 protein in a time-dependent manner (p < 0.05). The PAI-1 staining in gingival tissue was stronger in the cyclosporin A-induced gingival overgrowth group than in the normal gingival group (p < 0.05). In the cyclosporin A-induced gingival overgrowth group, intensive staining for PAI-1 expression was observed mainly in the cytoplasm of fibroblasts, endothelial cells and inflammatory cells.


CONCLUSIONS
These findings suggest that the up-regulation of PAI-1 may play an important part in the molecular pathogenesis of cyclosporin A-induced gingival overgrowth.
Lin
H-J
HJ
Institute of Stomatology, College of Oral Medicine, Chung Shan Medical University, Taichung, Taiwan.
Tsai
C-H
CH
Huang
F-M
FM
Chang
Y-C
YC
D002478:Cells, Cultured; D004396:Coloring Agents; D016572:Cyclosporine / Q000494:pharmacology*; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D005881:Gingiva / Q000166:cytology / Q000187:drug effects*; D019214:Gingival Overgrowth / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007249:Inflammation; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects*
D004396:Coloring Agents; D007166:Immunosuppressive Agents; D017395:Plasminogen Activator Inhibitor 1; D016572:Cyclosporine