Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India.
PLoS One. 2012;7(12):e51806. doi: 10.1371/journal.pone.0051806. Epub 2012 Dec 19.
Oral submucous fibrosis (OSF) is a chronic inflammatory disease characterized by the accumulation of excess collagen, and areca nut chewing has been proposed as an important etiological factor for disease manifestation. Activation of transforming growth factor-β signaling has been postulated as the main causative event for increased collagen production in OSF. Oral epithelium plays important roles in OSF, and arecoline has been shown to induce TGF-β in epithelial cells. In an attempt to understand the role of areca nut constituents in the manifestation of OSF, we studied the global gene expression profile in epithelial cells (HaCaT) following treatment with areca nut water extract or TGF-β. Interestingly, 64% of the differentially regulated genes by areca nut water extract matches with the TGF-β induced gene expression profile. Out of these, expression of 57% of genes was compromised in the presence of ALK5 (TβRI) inhibitor and 7% were independently induced by areca nut, highlighting the importance of TGF-β in areca nut actions. Areca nut water extract treatment induced p-SMAD2 and TGF-β downstream targets in HaCaT cells but not in human gingival fibroblast cells (hGF), suggesting epithelial cells could be the source of TGF-β in promoting OSF. Water extract of areca nut consists of polyphenols and alkaloids. Both polyphenol and alkaloid fractions of areca nut were able to induce TGF-β signaling and its downstream targets. Also, SMAD-2 was phosphorylated following treatment of HaCaT cells by Catechin, Tannin and alkaloids namely Arecoline, Arecaidine and Guvacine. Moreover, both polyphenols and alkaloids induced TGF-β2 and THBS1 (activator of latent TGF-β) in HaCaT cells suggesting areca nut mediated activation of p-SMAD2 involves up-regulation and activation of TGF-β. These data suggest a major causative role for TGF-β that is induced by areca nut in OSF progression.
口腔黏膜下纤维性变（OSF）是一种慢性炎症性疾病，其特征是过量胶原蛋白的积累，而槟榔咀嚼已被提出是疾病表现的重要病因。转化生长因子-β信号的激活被认为是 OSF 中胶原蛋白产生增加的主要原因。口腔上皮在 OSF 中起着重要作用，并且已经表明槟榔碱可诱导上皮细胞中的 TGF-β。为了了解槟榔成分在 OSF 表现中的作用，我们研究了上皮细胞（HaCaT）在用槟榔水提取物或 TGF-β处理后的全基因表达谱。有趣的是，槟榔水提取物调节的基因中有 64%与 TGF-β诱导的基因表达谱相匹配。在这些基因中，57%的基因在存在 ALK5（TβRI）抑制剂的情况下表达受损，而 7%的基因则独立地被槟榔诱导，这突出了 TGF-β在槟榔作用中的重要性。槟榔水提取物处理诱导了 HaCaT 细胞中的 p-SMAD2 和 TGF-β下游靶标，但不在人牙龈成纤维细胞（hGF）中诱导，这表明上皮细胞可能是促进 OSF 的 TGF-β的来源。槟榔水提取物包含多酚和生物碱。槟榔的多酚和生物碱部分均能诱导 TGF-β 信号及其下游靶标。此外，在用儿茶素、单宁和生物碱（槟榔碱、槟榔次碱和古瓦碱）处理 HaCaT 细胞后，SMAD-2 被磷酸化。此外，多酚和生物碱均诱导 HaCaT 细胞中的 TGF-β2 和 THBS1（潜伏 TGF-β 的激活剂），这表明槟榔介导的 p-SMAD2 激活涉及 TGF-β 的上调和激活。这些数据表明 TGF-β在 OSF 进展中起主要的致病作用，而 TGF-β是由槟榔诱导的。
