Wu King-Jean, Huang Guay-Fen, Chen Chun-Hao, Chang Hao-Hueng, Deng Yi-Ting
Department of Dentistry, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan.
Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan.
J Formos Med Assoc. 2014 Nov;113(11):828-32. doi: 10.1016/j.jfma.2014.01.008. Epub 2014 Feb 20.
BACKGROUND/PURPOSE: Transforming growth factor-β (TGF-β) plays an important role in the pathogenesis of cyclosporine A (CsA)-induced gingival overgrowth (GO). Connective tissue growth factor (CTGF/CCN2) acts as a cofactor with TGF-β to induce the maximal profibrotic effects of TGF-β. We investigated the effects of CsA on CCN2 expression in human gingival fibroblasts (HGFs) and the potential chemopreventive agent for CsA-induced GO.
Western blot analyses were used to examine the signaling pathways of CsA-induced CCN2 expression in HGFs and whether epigallocatechin-3-gallate (EGCG), curcumin, or lovastatin can inhibit CsA-induced CCN2 expression.
CsA significantly stimulated CCN2 synthesis in HGFs. This effect can be inhibited by c-Jun NH(2)-terminal kinase (JNK) and Smad3 inhibitors but not by TGF-β neutralizing antibody and TGF-β type I receptor inhibitor. Furthermore, EGCG completely blocked CsA-induced CCN2 expression.
CsA-induced CCN2 protein expression is mediated through JNK and Smad signaling. CsA may contribute to the pathogenesis of GO through upregulation of CCN2 expression in HGFs. EGCG could be an adjuvant for the prevention of CsA-induced GO.
背景/目的：转化生长因子-β（TGF-β）在环孢素A（CsA）诱导的牙龈过度生长（GO）发病机制中起重要作用。结缔组织生长因子（CTGF/CCN2）作为TGF-β的辅助因子，可诱导TGF-β产生最大的促纤维化作用。我们研究了CsA对人牙龈成纤维细胞（HGFs）中CCN2表达的影响以及CsA诱导的GO的潜在化学预防剂。
采用蛋白质印迹分析检测CsA诱导HGFs中CCN2表达的信号通路，以及表没食子儿茶素-3-没食子酸酯（EGCG）、姜黄素或洛伐他汀是否能抑制CsA诱导的CCN2表达。
CsA显著刺激HGFs中CCN2的合成。这种作用可被c-Jun氨基末端激酶（JNK）和Smad3抑制剂抑制，但不能被TGF-β中和抗体和TGF-βⅠ型受体抑制剂抑制。此外，EGCG完全阻断了CsA诱导的CCN2表达。
CsA诱导的CCN2蛋白表达通过JNK和Smad信号介导。CsA可能通过上调HGFs中CCN2的表达促进GO的发病机制。EGCG可能是预防CsA诱导的GO的辅助药物。
