INTERACTIONS BETWEEN TUMOR NECROSIS FACTOR-ALPHA, HYPOTHALAMIC CORTICOTROPIN-RELEASING HORMONE, AND ADRENOCORTICOTROPIN SECRETION IN THE RAT
INTERACTIONS BETWEEN TUMOR NECROSIS FACTOR-ALPHA, HYPOTHALAMIC CORTICOTROPIN-RELEASING HORMONE, AND ADRENOCORTICOTROPIN SECRETION IN THE RAT
复制标题
DOI：
10.1210/endo-126-6-2876
复制
发表时间：
1990-06-01
期刊：
影响因子：
4.8
通讯作者：
CHROUSOS, GP
中科院分区：
文献类型：
--
作者：
BERNARDINI, R;KAMILARIS, TC;CHROUSOS, GP
我们研究了肿瘤坏死因子-α的作用。（TNF α），一种巨噬细胞衍生的多效性细胞因子，在炎症/免疫应答期间产生，对大鼠下丘脑-垂体-肾上腺（HPA）轴的功能起作用。静脉注射TNF α。以剂量依赖性方式刺激血浆ACTH和皮质酮分泌。这种作用被在TNF α前1小时给予大鼠的大鼠CRH抗血清抑制。注射剂这表明CRH是HPA轴对TNF α反应的主要介质。我们随后评估了TNF α的能力。分别用器官培养的大鼠下丘脑和原代培养的大鼠垂体前叶细胞对CRH和ACTH分泌的影响。将下丘脑与分级浓度的TNF α（10 pM至1 μ M）孵育40分钟。该细胞因子以剂量依赖性方式刺激CRH分泌，EC 50为6.7x 10 pM（P < 0.05）。下丘脑外植体与地塞米松、吲哚美辛（1 μ M）、二十碳四炔酸（10 μ M）或去甲二氢愈创木酸（30 μ M）的预温育导致TNF α-刺激CRH分泌（P < 0.05）。有趣的是，用TNF α孵育4小时，浓度为10 nM时，对大鼠前垂体细胞的ACTH分泌无影响。较高浓度的TNF α。(100然而，在培养基中，浓度为1 nM和1 μ M的促肾上腺皮质激素（ACTH）引起了剂量依赖性的增加。我们的结果表明TNF α。代表在免疫/炎症反应期间直接或通过刺激其他细胞因子作为HPA轴激活剂的免疫应答介质之一。这种作用似乎是糖皮质激素抑制和类花生酸介导的。TNFa的主要作用部位似乎是下丘脑分泌CRH的神经元。TNF α的一些垂体和肾上腺作用，然而，不能排除。
We studied the effects of tumor necrosis factor-.alpha. (TNF.alpha.), a macrophage-derived pleiotropic cytokine produced during the inflammatory/immune response, on the function of the hypothalamic-pituitary-adrenal (HPA) axis of the rat. Intravenous injections of TNF.alpha. stimulated plasma ACTH and corticosterone secretion in a dose-dependent fashion. This effect was inhibited by a rat CRH antiserum that was administered to the rats 1 h before the TNF.alpha. injections. This suggested that CRH is a major mediator of the HPA axis response to TNF.alpha.. We subsequently evaluated the ability of TNF.alpha. to influence CRH and ACTH secretion in vitro by explanted rat hypothalami in organ-culture and by dispersed rat anterior pituicytes in primary culture respectively. Hypothalami were incubated for 40 min with graded concentrations of TNFa (10 pM to 1 .mu.M). This cytokine stimulated CRH secretion in a dose-dependent fashion, with an EC50 of 6.7 .times. 10 pM (P < 0.05). Preincubation of hypothalamic explants with dexamethasone, indomethacin (1 .mu.M), eicosatetraynoic acid (10 .mu.M), or nordihydroguaiaretic acid (30 .mu.M) resulted in inhibition of TNF.alpha.-stimulated CRH secretion (P < 0.05). Interestingly, 4-h incubation with TNF.alpha. had no effect on ACTH secretion from rat anterior pituicytes at a concentration of 10 nM. Higher concentrations of TNF.alpha. (100 nM and 1 .mu.M), however, elicited a dose-dependent increase in the ACTH concentration in the medium. Our results suggest that TNF.alpha. represents one of the immune response mediators that directly or via stimulation of other cytokines act as activators of the HPA axis during immune/inflammatory reactions. This effect appears to be glucocorticoid suppressible and eicosanoid mediated. The primary site of action of TNFa appears to be the hypothalamic CRH-secreting neuron. Some pituitary and adrenal effects of TNF.alpha., however, cannot be excluded.