SIGNALING CROSSTALK AND THYROID CELL SURVIVAL

免疫介导的细胞破坏是自身免疫性疾病发展的中心病理事件之一。桥本甲状腺炎（HT）中，对甲状腺抗原的特异性免疫反应导致淋巴细胞浸润、滤泡细胞破坏和临床甲状腺功能减退。现在很明显，细胞凋亡是HT和其他自身免疫性疾病的主要病理机制之一。促炎细胞因子被认为在自身免疫和细胞凋亡中起起始作用。干扰素- γ (ifn - γ)和白细胞介素- 1- β参与了HT和其他自身免疫性疾病的发病机制。最近，这些细胞因子被证明可以诱导Fas受体在正常人甲状腺细胞（FasL的表达细胞）上表达。Fas交联导致大量细胞凋亡，推测在炎症和细胞因子释放后，甲状腺细胞通过自相残杀机制被修剪死亡。促甲状腺激素（TSH）调节甲状腺功能、增殖和可能的生存。TSH刺激甲状腺特异性基因的表达，这种作用与（ifn - γ）相反。反过来，据报道，TSH可以降低ifn - γ对Fas表达和凋亡的影响。我们的目的是阐明促炎细胞因子在连续的大鼠甲状腺细胞中的作用。我们希望利用生物化学、细胞生物学和显微注射相结合的方法来探索细胞因子诱导的细胞死亡和TSH促进细胞存活的机制。考虑到细胞因子和激素对Fas表达的相反作用，它们之间的相互作用可能会显著改变内分泌细胞对凋亡的易感性，这是一个对甲状腺炎、糖尿病和类风湿性关节炎等自身免疫性疾病具有深远影响的因素。Ras激活是甲状腺癌中常见的事件，它使许多细胞对细胞因子诱导的凋亡敏感，许多研究表明Ras和Fas激活的信号之间存在密切联系。TSH似乎改变了Ras介导的信号从增殖到凋亡的平衡，这一发现可能解释了在甲状腺肿瘤中Ras和Gs或TSH受体突变的罕见发生，突变导致cAMP介导的信号通路的组成活性。我们将研究Ras对细胞凋亡的急性作用，以及负责这些作用的信号通路。我们将确定有助于ras转化细胞逃避凋亡能力的细胞因子。综上所述，这些研究将为甲状腺细胞存活和转化的调控提供新的见解，并适用于其他内分泌细胞。

Immune-mediated cell destruction is one of the central pathologic events in the development of autoimmune disease. In Hashimoto's thyroiditis (HT), a specific immune response to thyroid antigens leads to lymphocytic infiltration, follicular cell destruction and clinical hypothyroidism. It is now evident that apoptosis is one of the major pathologic mechanisms underlying HT and other forms of autoimmune disease. Proinflammatory cytokines are thought to play an initiating role in autoimmunity and apoptosis. Interferon-gamma (IFN-gamma) and interleukin 1-beta have been implicated in the pathogenesis of HT and other autoimmune disorders. Recently, these cytokines were shown to induce Fas receptor expression on normal human thyrocytes, cells that express FasL. Cross-linking of Fas resulted in massive apoptosis, leading to the speculation that following inflammation and cytokine release, thyroid cells are pruned to die by fratricidal mechanisms. Thyrotropin (TSH) regulates thyroid function, proliferation and possibly, survival. TSH stimulates the expression of thyroid-specific genes, effects that are opposed by (IFN-gamma). In turn, TSH has been reported to decrease IFN-gamma effects on Fas expression and apoptosis. Our aims are to elucidate the effects of proinflammatory cytokines in a continuous line of rat thyroid cells. We wish to explore the mechanisms of cytokine-induced cell death, and of survival promoted by TSH using a combination of biochemistry, cell biology and microinjection. Crosstalk between cytokines and hormones, given their opposing effects on Fas expression, may significantly alter the susceptibility of endocrine cells to apoptosis, a factor with profound implications for autoimmune diseases including thyroiditis, diabetes and rheumatoid arthritis. Ras activation, a frequent event in thyroid cancer, sensitizes many cells to cytokine-induced apoptosis, and numerous studies implicate a close linkage between signals activated by Ras and Fas. TSH appears to alter the balance in Ras-mediated signals from proliferation to apoptosis, a finding that may explain the infrequent occurrence of mutations in Ras and in Gs or the TSH receptor, mutations leading to the constitutive activity cAMP- mediated signaling pathways, in thyroid tumors. We will examine the acute effects of Ras on apoptosis, and the signaling pathways responsible for these effects. We will identify cellular factors that contribute to the ability of Ras-transformed cells to escape apoptosis. Taken together, these studies will provide new insight into the regulation of thyroid cell survival and transformation applicable to other endocrine cells.