Regulation of type I plasminogen activator inhibitor in human gingival fibroblasts with cyclosporine A.
OBJECTIVE
Cyclosporine A (CsA) is used as an immunosuppressive agent and its prominent side effect is the induction of gingival overgrowth. Type I plasminogen activator inhibitor (PAI-1) has shown to play an important role in CsA-induced gingival overgrowth. However, little is known about whether factors can modulate CsA-induced PAI-1 expression.


METHODS
Cytotoxicity, reverse transcriptase-polymerase chain reaction, and enzyme-linked immunosorbent assay were used to investigate the effects of Human gingival fibroblasts (HGFs) exposed to CsA. In addition, Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, interlukin-1alpha, tumor necrosis factor-alpha, mitogen-activated protein kinase kinase (MEK) inhibitor U0126, signal-regulated protein kinase (ERK) inhibitor PD98059 and cell-permeable glutathione precursor N-acetyl-L-cysteine (NAC) were added to test how they modulated the effects of CsA-induced PAI-1 expression.


RESULTS
The concentration of CsA higher than 500 ng ml(-1) demonstrated cytotoxicity to HGFs (P < 0.05). Periodontal pathogens as well as proinflammatory cytokines were found to increase the CsA-induced PAI-1 mRNA and protein expression (P < 0.05). Pharmacological agents NAC, U0126, and PD98059 were found to decrease the CsA-induced PAI-1 mRNA and protein expression (P < 0.05).


CONCLUSIONS
Cyclosporine A (CsA) may predispose to gingival overgrowth under inflammatory environments. The regulation of PAI-1 expression induced by CsA might be critically related with the intracellular glutathione and the ERK-MAPK pathway.
Ho
Y-C
YC
School of Applied Chemistry, Chung Shan Medical University, Taichung, Taiwan.
Lin
H-J
HJ
Tsai
C-H
CH
Chang
Y-C
YC
D002478:Cells, Cultured; D016572:Cyclosporine / Q000009:adverse effects / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005881:Gingiva / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005886:Gingival Hypertrophy / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis
D007166:Immunosuppressive Agents; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D016572:Cyclosporine