Cyclosporin A induces proliferation in human gingival fibroblasts via induction of transforming growth factor-beta1.
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-beta1). In this study, we evaluated the effects of CsA and TGF-beta1 on human normal gingival (NG) fibroblast proliferation, and explored a possible autocrine stimulation of TGF-beta1 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-beta1 and the proliferation index determined by automatic cell counting, BrdU incorporation, PCNA expression, and mitotic potential. To determine the effect of TGF-beta1 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-beta1 mRNA.


RESULTS
Treatment of NG fibroblasts with CsA or TGF-beta1 significantly stimulated the cell proliferation in a dose-dependent manner. Furthermore, neutralization of TGF-beta1 production in CsA-treated NG fibroblasts inhibited CsA's effect on NG fibroblast proliferation, demonstrating an autocrine stimulatory effect of TGF-beta1 in CsA-treated NG fibroblast proliferation.


CONCLUSIONS
The results presented here suggest that CsA stimulatory induction of NG fibroblast proliferation is mediated via TGF-beta1 in an autocrine fashion.
Cotrim
P
P
Discipline of Oral Pathology, University of Campinas Dental School, Piracicaba, São Paulo, Brazil.
Martelli-Junior
H
H
Graner
E
E
Sauk
J J
JJ
Coletta
R D
RD
D000704:Analysis of Variance; D000963:Antimetabolites; D019898:Autocrine Communication / Q000187:drug effects; D001973:Bromodeoxyuridine; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects*; D005881:Gingiva / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008940:Mitotic Index; D016376:Oligonucleotides, Antisense; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D014176:Protein Biosynthesis / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
D000963:Antimetabolites; D007166:Immunosuppressive Agents; D016376:Oligonucleotides, Antisense; D018809:Proliferating Cell Nuclear Antigen; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016572:Cyclosporine; D001973:Bromodeoxyuridine