Endogenous cortisol determines the circadian rhythm of lipopolysaccharide- but not lipoteichoic acid-inducible cytokine release
Endogenous cortisol determines the circadian rhythm of lipopolysaccharide- but not lipoteichoic acid-inducible cytokine release
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DOI：
10.1002/eji.200535470
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发表时间：
2006-02-01
影响因子：
5.4
通讯作者：
Hartung, T
中科院分区：
文献类型：
--
作者：
Hermann, C;von Aulock, S;Hartung, T
为了研究诱导细胞因子释放的昼夜节律和内源性皮质醇的潜在起搏器作用，对 11 名志愿者在 24 小时内以 4 小时的间隔评估皮质醇水平以及离体 LPS 刺激的血液中的细胞因子释放。我们发现 IFN-γ 和 IL-8 存在显着的昼夜变化，TNF 也有趋势，所有这些都与血清皮质醇水平呈负相关，但没有证据表明 IL-1 β 和 IL-6 存在这种节律。氢化可的松 (HC) 抑制细胞因子的体外 IC50 值与观察到的昼夜节律排序相对应。 mRNA 分析表明这是由于基因转录减少所致。 HC 的这些作用可被糖皮质激素受体拮抗剂 RU486 显着逆转。体内补充 HC 以维持全天早晨皮质醇水平，会减弱离体 LPS 诱导的细胞因子的昼夜节律。令人惊讶的是，在用脂磷壁酸（LTA）（LPS 的革兰氏阳性对应物）刺激后，在同一志愿者组中没有发现任何研究的细胞因子存在显着的昼夜变化。此外，与 LPS 相比，需要高 10-50 倍的 HC 浓度才能阻止 LTA 诱导的细胞因子释放。与 LPS 相比，LTA 无法激活 Jun 激酶，据报道，这是 HC 作用的靶点。
To investigate the circadian rhythm of inducible cytokine release and a potential pacemaker role of endogenous cortisol, cortisol levels as well as cytokine release from ex vivo LPS-stimulated blood were assessed at 4-h intervals over 24 h in 11 volunteers. We found a significant diurnal variation for IFN-gamma and IL-8, and a tendency for TNF, all inversely correlated to the serum cortisol levels, but no evidence for such a rhythm for IL-1 beta and IL-6. In vitro IC50 values for cytokine inhibition by hydrocortisone (HC) corresponded to the observed rank order for circadian rhythmicity. mRNA analyses revealed that this was due to a reduction of gene transcription. These effects of HC were significantly reversed by the glucocorticoid receptor antagonist RU486. Supplementation of HC in vivo to maintain morning cortisol levels throughout the day blunted the circadian rhythm of ex vivo LPS-induced cytokines. Surprisingly, no significant diurnal variation for any investigated cytokine was found in the same volunteer group upon stimulation with lipoteichoic acid (LTA), the gram-positive counterpart to LPS. Furthermore, 10-50-fold higher HC concentrations as compared to LPS were required to block LTA-induced cytokine release. LTA, in contrast to LPS, failed to activate Jun kinase, a reported target for HC action.