Crofford L J, Kalogeras K T, Mastorakos G, Magiakou M A, Wells J, Kanik K S, Gold P W, Chrousos G P, Wilder R L
Inflammatory Joint Diseases Section, National Institute of Arthritis and Musculoskeletal and Skin Disease, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Clin Endocrinol Metab. 1997 Apr;82(4):1279-83. doi: 10.1210/jcem.82.4.3852.
Systemic symptoms in rheumatoid arthritis (RA) are mediated, at least in part, by elevated levels of circulating interleukin (IL)-6, and this cytokine is also a potent stimulus of the hypothalamic-pituitary-adrenal axis. To evaluate the 24-h circadian secretory dynamics of ACTH, cortisol, and IL-6 and their interactions in patients with early untreated RA, we recruited and studied five newly diagnosed, untreated RA patients early in the course of their disease and five age-, gender-, and race-matched control subjects. We collected serial blood samples over 24 h and measured plasma ACTH and cortisol every 30 min and IL-6 every hour. The 24-h collection was followed by administration of ovine CRH (oCRH) and post-oCRH serial blood samples over 2 h. We analyzed the 24-h overall levels of these hormones and their circadian variations and performed time-lagged cross-correlation analyses among them. The untreated RA patients had 24 h time-integrated plasma ACTH, plasma cortisol levels, and urinary free cortisol excretion that were not significantly different from control subjects, in spite of their disease activity. However, an earlier morning surge of plasma ACTH and cortisol in the patients was suggested. Plasma ACTH and cortisol responses to oCRH were similar in RA patients and controls. IL-6 levels were significantly increased in the RA patients compared with control subjects during the early morning hours (P < 0.05). There was pronounced circadian variation of plasma Il-6 levels. In the RA patients, we detected a positive temporal correlation between plasma levels of IL-6 and ACTH/cortisol, with elevated levels of IL-6 before the elevations of ACTH and cortisol by 1 and 2 h, respectively. In the same patients, we detected a negative effect of cortisol upon IL-6 exerted with a delay of 5 h. The data presented here suggest that although endogenous IL-6 may stimulate secretion of ACTH and cortisol, overall activity of the hypothalamic-pituitary-adrenal axis remains normal and apparently is insufficient to inhibit ongoing inflammation in early untreated RA patients.
类风湿关节炎（RA）的全身症状至少部分是由循环白细胞介素（IL）-6水平升高介导的，并且这种细胞因子也是下丘脑-垂体-肾上腺轴的有力刺激物。为了评估早期未治疗的RA患者促肾上腺皮质激素（ACTH）、皮质醇和IL-6的24小时昼夜分泌动态及其相互作用，我们招募并研究了五名新诊断的、未治疗的处于疾病早期的RA患者以及五名年龄、性别和种族匹配的对照受试者。我们在24小时内采集系列血样，每30分钟测量血浆ACTH和皮质醇，每小时测量IL-6。24小时采集后给予羊促肾上腺皮质激素释放激素（oCRH），并在注射oCRH后2小时内采集系列血样。我们分析了这些激素的24小时总体水平及其昼夜变化，并对它们进行了时间滞后交叉相关分析。尽管未治疗的RA患者有疾病活动，但他们的24小时血浆ACTH时间积分、血浆皮质醇水平和尿游离皮质醇排泄与对照受试者无显著差异。然而，提示患者血浆ACTH和皮质醇在清晨有较早的高峰。RA患者和对照受试者对oCRH的血浆ACTH和皮质醇反应相似。与对照受试者相比，RA患者在清晨时IL-6水平显著升高（P<0.05）。血浆IL-6水平有明显的昼夜变化。在RA患者中，我们检测到IL-6血浆水平与ACTH/皮质醇之间存在正的时间相关性，IL-6水平分别在ACTH和皮质醇升高前1小时和2小时升高。在同一患者中，我们检测到皮质醇对IL-6有延迟5小时的负向作用。此处呈现的数据表明，尽管内源性IL-6可能刺激ACTH和皮质醇的分泌，但下丘脑-垂体-肾上腺轴的总体活性仍保持正常，显然不足以抑制早期未治疗的RA患者持续的炎症反应。
