NADPH Oxidase 4 Mediates TGF beta 1-induced CCN2 in Gingival Fibroblasts

作者：Yang W H^*; Deng Y T; Hsieh Y P; Wu K J; Kuo M Y P

来源：Journal of Dental Research, 2015, 94(7): 976-982.

DOI：10.1177/0022034515580986

• chemoprevention
• curcumin
• fibrosis
• gingival overgrowth
• reactive oxygen species
• signal transduction

Transforming growth factor beta (TGF beta) plays a central role in the pathogenesis of gingival overgrowth (GO). Connective tissue growth factor (CTGF; or CCN2) is induced by TGF beta in human gingival fibroblasts (HGFs) and is overexpressed in GO tissues. CCN2 creates an environment favorable for fibrogenesis and is required for the maximal profibrotic effects of TGF beta. We previously showed that Src, JNK, and Smad3 mediate TGF beta 1-induced CCN2 protein expression in HGFs. Moreover, Src is an upstream signaling transducer of JNK and Smad3. Recent studies suggested that NADPH oxidase (NOX)-dependent redox mechanisms are involved in mediating the profibrotic effects of TGF beta. In this study, we demonstrated that TGF beta 1 upregulated NOX4 protein expression and increased reactive oxygen species (ROS) production in HGFs. Genetic or pharmacologic targeting of NOX4 abrogated TGF beta 1-induced ROS production; Src, JNK, and Smad3 activation; and CCN2 and type I collagen protein expression in HGFs. Our results indicated that NOX4-derived ROS play pivotal roles in activating Src kinase activity leading to the activation of canonical (Smad3) and noncanonical (JNK) cascades that cooperate to attain maximum CCN2 expression. Furthermore, we demonstrated that curcumin significantly inhibited the TGF beta 1-induced NOX4 protein expression in HGFs. Curcumin potentially qualifies as an agent to control GO by suppressing TGF beta 1-induced NOX4 expression in HGFs.

• 出版日期2015-7