Jeng Jiiang-Huei, Wang Ying-Jan, Chiang Bor-Luen, Lee Po-Hsuen, Chan Chiu-Po, Ho Yuan-Soon, Wang Tong-Mei, Lee Jang-Jaer, Hahn Liang-Jiunn, Chang Mei-Chi
Laboratory of Dental Pharmacology and Toxicology, Department of Dentistry, National Taiwan University Hospital and National Taiwan University College of Medicine, Taiwan.
Carcinogenesis. 2003 Aug;24(8):1301-15. doi: 10.1093/carcin/bgg083. Epub 2003 May 22.
Betel quid (BQ) chewing is an etiologic factor of oral cancer and submucus fibrosis (OSF). Keratinocyte inflammation is crucial for the pathogenesis of cancer and tissue fibrosis. We found that areca nut (AN) extract (100-400 micro g/ml) induced PGE2 production by KB cells by 2.34- to 23.1-fold and also TNF-alpha production by gingival keratinocytes (GK). Arecoline (0.2-1.2 mM) elevated PGE2 production by KB cells by 2.5- to 6.1-fold. AN extract (200-400 micro g/ml) also induced IL-6 production by GK (7.5- to 8.4-fold) and KB cells. In contrast, arecoline (0.1-1.2 mM) suppressed IL-6 production by GK and KB cells, with 42-81 and 41-63% inhibition, respectively. A 48 h exposure of GK to 800-1200 micro g/ml AN extract led to 37-69% cell death. Arecoline cytotoxicity to GK was noted at concentrations of 0.8-1.2 mM, which led to 28-38% cell death. AN extract (400-800 micro g/ml) induced Cox-2 and IL-6 mRNA expression and also COX-2 protein production by KB cells. IL-6 (5-100 ng/ml) suppressed GK growth by 20-33%, but enhanced oral fibroblast (OMF) and KB cell growth. PGE2 (0.05-5 micro g/ml) and anti-IL-6 antibody (ab) (50-1000 ng/ml) showed little effect on GK and KB cell growth. Incubation of GK and KB cells with aspirin, anti-IL-6 ab and anti-TNF-alpha ab showed little effect on arecoline- and AN-induced cytotoxicity, cell cycle arrest and apoptosis. Exposure to anti-TNF-alpha ab slightly affected arecoline- and AN-modulated PGE2 and IL-6 production by GK and KB cells. Arecoline- and AN-conditioned medium decreased phytohemagglutinin-mediated CD4+ and CD8+ T cell activation. These results indicate that BQ chewing contributes to the pathogenesis of cancer and OSF by impairing T cell activation and by induction of PGE2, TNF-alpha and IL-6 production, which affect oral mucosal inflammation and growth of OMF and oral epithelial cells.
嚼槟榔是口腔癌和口腔黏膜下纤维化（OSF）的一个病因。角质形成细胞炎症对于癌症和组织纤维化的发病机制至关重要。我们发现，槟榔提取物（100 - 400微克/毫升）可使KB细胞产生的前列腺素E2（PGE2）增加2.34至23.1倍，也可使牙龈角质形成细胞（GK）产生肿瘤坏死因子-α（TNF-α）。槟榔碱（0.2 - 1.2毫摩尔）使KB细胞产生的PGE2增加2.5至6.1倍。槟榔提取物（200 - 400微克/毫升）还可诱导GK（7.5至8.4倍）和KB细胞产生白细胞介素-6（IL-6）。相比之下，槟榔碱（0.1 - 1.2毫摩尔）抑制GK和KB细胞产生IL-6，抑制率分别为42%至81%和41%至63%。GK细胞暴露于800 - 1200微克/毫升的槟榔提取物48小时会导致37%至69%的细胞死亡。槟榔碱对GK细胞的细胞毒性在浓度为0.8 - 1.2毫摩尔时被观察到，这会导致28%至38%的细胞死亡。槟榔提取物（400 - 800微克/毫升）诱导KB细胞中环氧合酶-2（Cox-2）和IL-6信使核糖核酸（mRNA）表达以及COX-2蛋白产生。IL-6（5 - 100纳克/毫升）使GK细胞生长抑制20%至33%，但增强口腔成纤维细胞（OMF）和KB细胞生长。PGE2（0.05 - 5微克/毫升）和抗IL-6抗体（ab）（50 - 1000纳克/毫升）对GK和KB细胞生长影响很小。用阿司匹林、抗IL-6 ab和抗TNF-α ab孵育GK和KB细胞对槟榔碱和槟榔提取物诱导的细胞毒性、细胞周期阻滞和细胞凋亡影响很小。暴露于抗TNF-α ab对槟榔碱和槟榔提取物调节的GK和KB细胞产生PGE2和IL-6有轻微影响。槟榔碱和槟榔条件培养基降低了植物血凝素介导的CD4 +和CD8 + T细胞活化。这些结果表明，嚼槟榔通过损害T细胞活化以及诱导PGE2、TNF-α和IL-6产生，从而促进癌症和OSF的发病机制，这些物质会影响口腔黏膜炎症以及OMF和口腔上皮细胞的生长。
