Mechanism of cyclosporine-induced overgrowth in gingiva.
Cyclosporine A (CsA) is a widely used immunosuppressant but with significant side-effects, such as gingival overgrowth. This study investigates how CsA induces gingival proliferation and shows the effects of the CsA-associated signaling messengers, IL-6 and TGF-beta1, on gingival proliferation. CsA increased both IL-6 and TGF-beta1 levels. In addition to CsA, an IL-6 or TGF-beta1 treatment also induced gingival fibroblast proliferation. Inhibiting the cytokine resulted in the suppression of CsA-induced proliferation. MAPKs and PI3K are known to be involved in cell proliferation. Therefore, the effect of CsA on the kinase activities was examined. The results showed that both p38 MAPK and PI3K are essential for gingival fibroblast proliferation. TGF-beta1 and IL-6 and their associated signaling transduction may be novel bona fide molecular targets for the prevention of gingival overgrowth in CsA-treated patients. (


BACKGROUND
MAPK, mitogen-activated protein kinase; P13K, phosphatidylinositol 3-kinase.)
Chae
H-J
HJ
Department of Dental Pharmacology and Wonkwang Biomaterial Implant Research Institute, School of Dentistry, Wonkwang University, Iksan, Chonbuk, South Korea;
Ha
M-S
MS
Yun
D-H
DH
Pae
H-O
HO
Chung
H-T
HT
Chae
S-W
SW
Jung
Y-K
YK
Kim
H-R
HR
D015152:Blotting, Northern; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects; D005881:Gingiva / Q000166:cytology / Q000187:drug effects*; D019214:Gingival Overgrowth / Q000139:chemically induced*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects
D007166:Immunosuppressive Agents; D015850:Interleukin-6; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016572:Cyclosporine; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4