REGULATION OF THYROID FUNCTION BY TRANSCRIPTION FACTOR NF-kappaB

1.感兴趣区清除系统在甲状腺癌中的作用已有研究表明，单核细胞可通过侵袭癌细胞分泌具有杀瘤作用的细胞因子。细胞因子的作用是通过产生活性氧中间体(ROI)来实现的。因此，癌细胞中的ROI清除系统可能具有拮抗细胞因子的细胞毒作用的能力。在这项研究中，我们研究了编码ROI清除剂的mRNAs的表达，如超氧化物歧化酶(SOD)和谷胱甘肽过氧化物酶(GPX)，并将它们的表达与肿瘤的淋巴转移等指标相关联。结果表明，在有淋巴转移的甲状腺癌细胞中，锰-超氧化物歧化酶的表达显著高于正常甲状腺组织。铜锌超氧化物歧化酶和GPX的表达与淋巴转移无关。未发现其与肿瘤局部侵袭及这些基因表达的相关性。因此，提示锰…的高表达乳头状癌细胞中更多的超氧化物歧化酶使它们在淋巴转移后存活。FRTL-5大鼠甲状腺细胞中核因子-kB活化机制的研究众所周知，细胞因子如肿瘤坏死因子-α和白介素6在自身免疫性甲状腺疾病的发生发展中起重要作用。另一个众所周知的事实是，高水平的促甲状腺激素会加剧这种紊乱。由于肿瘤坏死因子-α等细胞因子的作用是通过核因子-kB转位到核内(活化)来实现的，因此我们研究了TSH是否改变了肿瘤坏死因子-α对核因子-kB的激活。当FRTL-5细胞不受肿瘤坏死因子-α刺激时，未观察到核因子-kB的激活。单独用肿瘤坏死因子-α刺激时，仅在细胞核内观察到p50同源二聚体。促甲状腺激素和肿瘤坏死因子-α联合作用后，细胞核内出现p50-p65异源二聚体。P50是核因子-kB的一个亚家族，虽然具有DNA结合活性，但缺乏激活结构域。因此，p50同源二聚体在转录上是不活跃的。另一方面，p65既有DNA结合结构域，又有激活结构域。我们发现肿瘤坏死因子-α诱导p50-p65异源二聚体需要促甲状腺激素，提示抑制促甲状腺激素可能改善自身免疫性甲状腺疾病。促甲状腺激素对硫氧还蛋白(Trx)和氧化还原因子(Ref-1)的调节最近研究表明，核因子-kB的激活需要被Trx和Ref-1等酶还原。如上所述，TSH调节核因子-kB、肿瘤坏死因子-α的激活，研究TSH是否调节FRTL-5细胞中TRX和Ref-1的表达。结果表明，TSH可增加TRX和Ref-1的表达。较少

1. ROLE OF ROI-SCAVENGING SYSTEM IN THYROID CANCERIt has been shown that monocytes infiltrating cancer cells secret cytokines with cytocidal effect. The effect of cytokine is exerted by the production of reactive oxygen intermediates (ROI). It is thus possible that ROI-scavenging system in the cancer cell confer the ability to antagonize the cytotoxic effect of the cytokines. In this study, we investigated the expression of mRNAs coding for ROI-scavengers such as superoxide dismutase (SOD), glutathione peroxidase (GPX) and correlated their expression with indices for malignancies such as lymphatic metastasis. It was revealed that the expression of manganese-SOD mRNA was significantly higher in papillary thyroid cancer cells with lymphatic metastasis. There was no correlation with the expression of Copper-Zinc SOD and GPX with lymphatic metastasis. No correlation was found with local invasion and the expression of these mRNAs. It is thus suggested that the higher expression of manganese … More -SOD in papillary cancer cells renders them to survive after lymphatic metastasis.2. STUDIES ON THE MECHANISM FOR THE ACTIVATION OF NF-kB IN FRTL-5 RAT THYROID CELLSIt is well known that cytokines such as TNF-a and interleukin-6 play important role for the development of autoimmune thyroid disorder. Also known is the fact that high levels of thyroid stimulating hormone aggravate the disorder. Since the effect of cytokines such as TNF-a is mediated through tranlocation of Nuclear factor k B (NF-kB) into the nucleus (activation), it is studied whether TSH modifies the activation of NF-kB by TNF-a. When FRTL-5 cells were not stimulated by TNF-a, no activation of NF-kB was observed. When the cells were stimulated with TNF-a alone, only p50-homodimer was observed in the nuclei. Combined treatment of the cells with TSH and TNF-a resulted in the appearance of p50-p65 heterodimer in the nuclei. Although p50, a subfamily of NF-kB,has DNA-binding activity, it lacks activation domain. Therefore, p50 homodimer is transcriptionally inactive. On the other hand, p65 has both DNA-binding and activation domains. Our finding that induction of p50-p65 heterodimer by TNF-a requires TSH indicates that suppression of TSH in may improve autoimmune thyroid disorder.3. TSH-MEDIATED REGULATION OF THIOREDOXIN (TRX) AND REDOX FACTOR (Ref-1)It has been recently shown that activation of NF-kB requires reduction by the enzymes such as TRX and Ref-1. As mentioned above, TSH modulates the activation of NF-kB TNF-a, it is investigated whether TSH regulates the expression of TRX and Ref-1 in FRTL-5 cells. It was demonstrated that TSH increases the expression of both TRX and Ref-1. Less