Kasai K, Hattori Y, Nakanishi N, Manaka K, Banba N, Motohashi S, Shimoda S
Department of Endocrinology, Dokkyo University School of Medicine, Tochigi, Japan.
Endocrinology. 1995 Oct;136(10):4261-70. doi: 10.1210/endo.136.10.7545102.
We now report on the induction and modulation of NO production by cytokines in primary cultures of human thyrocytes and the effect of NO on iodine organification by human open thyroid follicles in the process of thyroid hormone biosynthesis. Although unstimulated thyrocytes produced little NO (measured as nitrite), interleukin-1 alpha or beta (IL-1 alpha/beta) substantially increased NO formation. Interferon-gamma (IFN-gamma) by itself failed to stimulate NO formation but markedly increased the IL-1-stimulated NO production. Tumor necrosis factor-alpha alone did not induce NO production but did so slightly in the presence of IFN-gamma. Induction of NO formation by thyrocytes upon stimulation with IL-1 alpha + IFN-gamma was accompanied by the synthesis of tetrahydrobiopterin (BH4), an obligatory cofactor of NOS. Coinduction of NO and BH4 synthesis in thyrocytes was preceded by coexpression of messenger RNAs for NOS and GTP cyclohydrolase I (GTPCH), the rate-limiting enzyme for de novo synthesis of BH4. NO synthesis was prevented by an inhibitor of GTPCH, 2,4-diamino-6-hydroxypyrimidine, and this inhibition was completely reversed by administration of sepiapterin, a substrate for BH4 synthesis via pterin salvage pathway. In contrast to IFN-gamma, some cytokines such as interferon-alpha, IL-4, and transforming growth factor-beta 1 inhibited the IL-1-induced NO production. Finally, a possible role of NO on thyroid hormone synthesis was investigated. Iodine organification by human open thyroid follicles was inhibited by two kinds of NO donor but not by cell permeable cyclicGMP analog. Thus, cytokines such as IL-1, IL-1/IFN-gamma, and tumor necrosis factor-alpha/IFN-gamma stimulate human thyrocytes to produce NO; this process can be modulated by other cytokines and coregulated with a cofactor BH4 biosynthesis, and resulting NO may affect cell function including thyroid hormone synthesis.
我们现在报告人甲状腺细胞原代培养中细胞因子对一氧化氮（NO）生成的诱导和调节作用，以及在甲状腺激素生物合成过程中NO对人开放甲状腺滤泡碘有机化的影响。尽管未受刺激的甲状腺细胞产生的NO很少（以亚硝酸盐衡量），但白细胞介素-1α或β（IL-1α/β）能显著增加NO的生成。干扰素-γ（IFN-γ）本身不能刺激NO生成，但能显著增加IL-1刺激的NO生成。单独的肿瘤坏死因子-α不能诱导NO生成，但在IFN-γ存在时能轻微诱导。IL-1α + IFN-γ刺激甲状腺细胞诱导NO生成的同时伴随着四氢生物蝶呤（BH4）的合成，BH4是一氧化氮合酶（NOS）的必需辅因子。甲状腺细胞中NO和BH4合成的共诱导之前是NOS和GTP环水解酶I（GTPCH）信使RNA的共表达，GTPCH是BH4从头合成的限速酶。GTPCH抑制剂2,4-二氨基-6-羟基嘧啶可阻止NO合成，通过蝶呤补救途径作为BH4合成底物的蝶酰三谷氨酸的给药可完全逆转这种抑制作用。与IFN-γ相反，一些细胞因子如干扰素-α、IL-4和转化生长因子-β1可抑制IL-1诱导的NO生成。最后，研究了NO对甲状腺激素合成的可能作用。两种NO供体可抑制人开放甲状腺滤泡的碘有机化，但细胞可渗透的环鸟苷酸类似物则无此作用。因此，如IL-1、IL-1/IFN-γ和肿瘤坏死因子-α/IFN-γ等细胞因子可刺激人甲状腺细胞产生NO；这一过程可被其他细胞因子调节，并与辅因子BH4生物合成共同调节，产生的NO可能影响包括甲状腺激素合成在内的细胞功能。
