Tumor necrosis factor-alpha-induced nitric oxide restrains the apoptotic response of anterior pituitary cells
Tumor necrosis factor-alpha-induced nitric oxide restrains the apoptotic response of anterior pituitary cells
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DOI：
10.1159/000081313
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发表时间：
2004-01-01
影响因子：
4.1
通讯作者：
Seilicovich, A
中科院分区：
文献类型：
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作者：
Candolfi, M;Jaita, G;Seilicovich, A
我们以前报道，肿瘤坏死因子-α（TNF-α）抑制细胞增殖，而它刺激垂体前叶细胞凋亡的雌激素依赖的方式。此外，我们发现，一氧化氮（NO）介导的TNF-α催乳素释放的抑制作用。本实验研究了TNF-α对周期性卵巢切除（OVX）大鼠垂体前叶细胞一氧化氮合酶（NOS）活性和表达的影响，以及NO在TNF-α诱导垂体前叶细胞凋亡中的作用。动情前期大鼠垂体前叶细胞NOS活性高于间情期，17 β-雌二醇（10（-9）M，E_2）可刺激NOS活性。TNF-α（50 ng/ml）刺激NOS活性的垂体前叶细胞从大鼠在两个阶段的动情周期和细胞从OVX大鼠培养或无E2。诱导型一氧化氮合酶（iNOS）基因在动情前期大鼠垂体前叶细胞中的表达高于动情间期，且其表达被TNF-α增强。OVX大鼠急性给予E2可增加垂体前叶内皮型一氧化氮合酶（eNOS）的表达。此外，E2增加分散的垂体前叶细胞eNOS mRNA，TNF-α阻断这种作用。nNOS在垂体前叶的表达在动情前期高于间情期，而eNOS在动情前期和间情期的表达相似。TNF-α降低动情前期和动情间期大鼠垂体前叶细胞eNOS mRNA的表达。在OVX大鼠的垂体前叶细胞中，TNF-α未能诱导细胞凋亡，但当细胞与NAME或NMMA（NOS抑制剂，不影响细胞活力本身）孵育时，TNF-α能够诱导细胞凋亡。在E2的存在下，NAME诱导细胞凋亡并增强TNF-α的促凋亡作用。总之，我们的研究表明，TNF-α上调iNOS基因的表达，而它下调雌激素诱导的eNOS在垂体前叶细胞的表达。内源性NO可能抑制而非介导TNF-α对垂体前叶细胞的促凋亡作用。版权所有（C）2004 S. Karger AG，巴塞尔。
We previously reported that tumor necrosis factor-alpha (TNF-alpha) inhibits cell proliferation whereas it stimulates apoptosis of anterior pituitary cells in an estrogen-dependent manner. Also, we showed that nitric oxide (NO) mediates the inhibitory effect of TNF-alpha on prolactin release. Here, we studied the effect of TNF-alpha on nitric oxide synthase (NOS) activity and expression in anterior pituitary cells from cycling and ovariectomized (OVX) rats, and the role of NO in TNF-alpha induced apoptosis of anterior pituitary cells. NOS activity was higher in anterior pituitary cells from rats in proestrus than in diestrus and was stimulated by 17beta-estradiol (10(-9) M, E2). TNF-alpha (50 ng/ml) stimulated NOS activity in anterior pituitary cells from rats at both stages of the estrous cycle and in cells from OVX rats cultured either with or without E2. Inducible NOS (iNOS) gene expression was higher in anterior pituitary cells from rats in proestrus than in diestrus and its expression was enhanced by TNF-alpha. Acute administration of E2 to OVX rats increased endothelial NOS (eNOS) expression in the anterior pituitary gland. Also, E2 increased eNOS mRNA in dispersed anterior pituitary cells from OVX rats, and this effect was blocked by TNF-alpha. nNOS expression in the anterior pituitary gland was higer at proestrus than at diestrus but eNOS expression was similar at both stages. TNF-alpha decreased eNOS mRNA in anterior pituitary cells from rats at proestrus or diestrus. In anterior pituitary cells from OVX rats, TNF-alpha failed to induce apoptosis but was able to induce it when cells were incubated with NAME or NMMA, NOS inhibitors that did not affect cell viability per se. In the presence of E2, NAME induced apoptosis and enhanced the proapoptotic effect of TNF-alpha. In conclusion, our study shows that TNF-alpha upregulates iNOS gene expression whereas it downregulates estrogen-induced eNOS expression in anterior pituitary cells. Endogenous NO may restrain rather than mediate the proapoptotic effect of TNF-alpha in anterior pituitary cells. Copyright (C) 2004 S. Karger AG, Basel.