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Mechanism of Cyclosporine-induced Overgrowth in Gingiva

¹ Department of Dental Pharmacology and Wonkwang Biomaterial Implant Research Institute, School of Dentistry, Wonkwang University, Iksan, Chonbuk, South Korea;
² Department of Pharmacology and Institute of Cardiovascular Research, Medical School, Chonbuk National University, Jeonju, Chonbuk, South Korea;
³ Department of Microbiology and Immunology, School of Medicine, Wonkwang University, Iksan, Chonbuk, South Korea; and
⁴ Department of Biological Science, Seoul National University, Seoul, South Korea

View larger version (33K): [in a new window]   Figure 1. . IL-6 and TGF-ß1 play an important role in CsA-induced proliferation in human gingival fibroblasts. (A) The cells were exposed to CsA (100 or 500 ng/mL), IL-6 (0.1 or 0.2 ng/mL), or TGF-ß1 (0.1 or 0.5 ng/mL) for 0, 3, 6, or 9 days, and were counted (mean ± SD; n = 5). (B) The cells were stimulated with 100 or 500 ng/mL CsA, 0.1 or 0.2 ng/mL IL-6, or 0.1 or 0.5 ng/mL TGF-ß1 for 6 days. The cells were then labeled with bromodeoxyuridine at four-hour intervals. The number of cells incorporating bromodeoxyuridine was counted (mean ± SD; n = 4). (C) The cells were treated with 500 ng/mL CsA, CsA+IL-6 neutralizing antibody (0.1 µg/mL), or CsA+TGF-ß1 neutralizing antibody (1 µg/mL) (mean ± SD; n = 4). (D) After the 500 ng/mL CsA treatment, the IL-6 and TGF-ß1 levels in the supernatants were measured (mean ± SD; n = 4). (B–D) *Significantly different from the control, p < 0.05. #Significantly different from CsA-treated, p < 0.05.

View larger version (36K): [in a new window]   Figure 2. CsA increased the activation of ERK, p38 MAPK, and PI3K in cells. (A) The cells were treated with 500 ng/mL CsA. Phosphorylated ERK1/2 and JNK1 levels were examined (a). The cells were treated with 500 ng/mL CsA in the presence or absence of 10 µM SB203580 (b). (B) CsA (500 ng/mL) was added for 5, 10, 20, 30, or 60 min. A PI3K activity assay was performed. (C) The cells either were untreated or were treated for 30 min with the indicated agents, followed by 24 hrs of stimulation with 500 ng/mL CsA. The IL-6 and TGF-ß1 levels in the supernatant were then measured (mean ± SD; n = 4). (D) The cells were treated with the indicated agents for 30 min, followed by stimulation with 500 ng/mL CsA for 3 days, and were then counted (mean ± SD; n = 6). *Significantly different from the CsA-treated, p < 0.05.

View larger version (27K): [in a new window]   Figure 3. . TGF-ß1 is a key factor in CsA-induced IL-6 release in human gingival fibroblasts. (A) The cells either were untreated or were treated for 30 min with TGF-ß1 (1 or 2 µg/mL) or IL-6 neutralizing antibody (0.1 µg/mL), followed by 24 or 48 hrs of stimulation with 500 ng/mL CsA. The supernatants were assayed for IL-6 (mean ± SD; n = 5). (B) The cells were treated with the IL-6 (0.1 or 0.2 µg/mL) or TGF-ß1 (1 µg/mL) neutralizing antibody, followed by 24 hrs of stimulation with 500 ng/mL CsA. The amount of TGF-ß1 in the supernatants was measured (mean ± SD; n = 3). *Significantly different from the CsA-treated, p < 0.05. (C) For the IL-6 assay, the cells were treated with 1, 5, or 10 ng/mL TGF-ß1 for 24 hrs (mean ± SD; n = 3). *Significantly different from the control, p < 0.05. #Significantly different from the CsA-treated, p < 0.05. (D) For the TGF-ß1 assay, the cells were incubated with 0.1, 0.5, or 1 µg/mL IL-6 for 24 hrs (mean ± SD; n = 3).

View larger version (14K): [in a new window]   Figure 4. Schematic diagram showing the signaling mechanism in CsA-induced gingival fibroblast proliferation.