Natarajan R, Ploszaj S, Horton R, Nadler J
Section of Endocrinology, University of Southern California, Los Angeles County Medical Center 90033.
Endocrinology. 1989 Dec;125(6):3084-9. doi: 10.1210/endo-125-6-3084.
Cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1), mediate many inflammatory and cellular responses. However, the effects of TNF and IL-1 on basal and angiotensin-II (AII)-stimulated aldosterone synthesis are not known. We studied the effect of recombinant and purified TNF and IL-1 on basal as well as AII-, ACTH-, and K+-induced aldosterone synthesis in isolated rat adrenal glomerulosa cells. Since we have previously shown that AII action is mediated by activation of the 12-lipoxygenase (12LO) pathway of arachidonic acid, we also evaluated the effects of these cytokines on the 12LO product 12-hydroxyeicosatetraenoic acid (12HETE) using a validated RIA technique. TNF at 2.5 and 5.0 ng/ml produced a dose-dependent inhibition of AII-induced aldosterone synthesis [AII, 39.0 +/- 3.3 ng/10(6) cells.h; AII plus TNF (5.0 ng/ml), 14.3 +/- 1.6; P less than 0.001 vs. AII; AII plus TNF (2.5 ng/ml), 24.7 +/- 3.2; P less than 0.01 vs. AII]. Similarly, TNF at 5.0 ng/ml also attenuated the stimulatory effect of ACTH (10(-9) M). However, K+-induced aldosterone synthesis was not altered. TNF also did not alter basal aldosterone levels. AII, as previously shown, stimulates 12HETE synthesis (basal, 608 +/- 114 pg/10(5) cells.h; versus AII, 1268 +/- 197; P less than 0.02). TNF at concentrations of 1.0-5.0 ng/ml produced a dose-dependent inhibition of AII stimulatory action on 12HETE synthesis [AII plus TNF (1.0 ng/ml), 650 +/- 26 pg, P less than 0.03 vs. AII; AII plus TNF (5.0 ng/ml), 390 +/- 46; P less than 0.01 vs. AII plus TNF (1.0 ng/ml)]. In addition, 12HETE at 10(-8) M completely restored the effects of AII during blockage by TNF. Purified human IL-1 (75% beta, 25% alpha) as well as recombinant human IL-1 beta at concentrations as low as 50 pg/ml inhibited AII-induced aldosterone synthesis. IL-1 beta did not alter ACTH- or K+-induced aldosterone synthesis and, in fact, had a tendency to potentiate ACTH effects. These results suggest that the cytokines TNF and IL-1 are potent inhibitors, particularly of AII action in the adrenal glomerulosa cell. Therefore, local or systemically produced TNF or IL-1 may be important negative modulators of aldosterone synthesis.
细胞因子如肿瘤坏死因子（TNF）和白细胞介素-1（IL-1）介导许多炎症和细胞反应。然而，TNF和IL-1对基础及血管紧张素-II（AII）刺激的醛固酮合成的影响尚不清楚。我们研究了重组和纯化的TNF及IL-1对分离的大鼠肾上腺球状带细胞基础以及AII、促肾上腺皮质激素（ACTH）和钾离子（K⁺）诱导的醛固酮合成的影响。由于我们之前已表明AII的作用是由花生四烯酸的12-脂氧合酶（12LO）途径的激活介导的，我们还使用经过验证的放射免疫分析（RIA）技术评估了这些细胞因子对12LO产物12-羟基二十碳四烯酸（12HETE）的影响。2.5和5.0 ng/ml的TNF对AII诱导的醛固酮合成产生剂量依赖性抑制作用[AII，39.0±3.3 ng/10⁶细胞·小时；AII加TNF（5.0 ng/ml），14.3±1.6；与AII相比，P<0.001；AII加TNF（2.5 ng/ml），24.7±3.2；与AII相比，P<0.01]。同样，5.0 ng/ml的TNF也减弱了ACTH（10⁻⁹M）的刺激作用。然而，K⁺诱导的醛固酮合成未改变。TNF也未改变基础醛固酮水平。如先前所示，AII刺激12HETE合成（基础，608±114 pg/10⁵细胞·小时；与AII相比，1268±197；P<0.02）。1.0 - 5.0 ng/ml浓度的TNF对AII刺激12HETE合成的作用产生剂量依赖性抑制作用[AII加TNF（1.0 ng/ml），650±26 pg，与AII相比，P<0.03；AII加TNF（5.0 ng/ml），390±46；与AII加TNF（1.0 ng/ml）相比，P<0.01]。此外，10⁻⁸M的12HETE在TNF阻断期间完全恢复了AII的作用。纯化的人IL-1（75%β，25%α）以及低至50 pg/ml浓度的重组人IL-1β抑制AII诱导的醛固酮合成。IL-1β未改变ACTH或K⁺诱导的醛固酮合成，实际上，有增强ACTH作用的趋势。这些结果表明细胞因子TNF和IL-1是强效抑制剂，特别是对肾上腺球状带细胞中AII的作用。因此，局部或全身产生的TNF或IL-1可能是醛固酮合成的重要负调节因子。
