Role of glucocorticoids and glucocorticoid receptor in priming of macrophages caused by glucocorticoid receptor blockade

We previously reported that glucocorticoid receptor (GR) blockade (injected with GR antagonist RU486) primed the host responses to lipopolysaccharide. Since decrease of GR and elevated glucocorticoids (GCs) have been always reported as parallel responses, we hypothesize that both GCs and GR play important roles in GR blockade induced priming. We first confirm that the production of nitric oxide (NO), superoxide (O₂⁻), and PKCα expression are all increased in peritoneal macrophages from GR blockade rats, indicating that macrophages are primed by GR blockade. Furthermore, using unilateral adrenalectomy rats, we find that the elevated GCs caused by a feedback mechanism following GR blockade may be involved in the process of priming. In vitro experiments in RAW264.7 cells show the inhibitory effect of GCs on NO production, which can be thoroughly blocked by RU486, indicating the increase of NO production in GR blockade rats is due to the elimination of GCs’s anti-inflammatory function. In contrast, 10⁻⁷ M corticosterone induces significant increases in O₂⁻ release, PKCα expression and phosphorylation, which cannot be reversed by RU486, demonstrating a previously unrecognized pro-inflammatory role of GCs in enhancing PM activation through a GR-independent pathway. The effect of GCs on PKCα expression even exists in GR deficient COS-7 cells as well as in GR knock-down RAW264.7 cells. In conclusion, both GR impairment and elevation of GCs are involved in the priming of macrophages caused by GR blockade. The findings of the divergent roles of GCs in modulation of inflammation may change therapeutic strategy for inflammatory diseases with GCs.     

Swimming exercise ameliorates depression-like behaviors induced by prenatal exposure to glucocorticoids in rats

Prenatal exposure to glucocorticoids (GCs) leads to affective dysfunction in adulthood, which may be associated with the alterations in hypothalamic–pituitary–adrenal (HPA) axis. Physical exercise has been shown to ameliorate depressive symptoms. The objectives of present study were to investigate whether prenatal exposure to GCs induces depression-like behaviors in adult offspring rats, and determine whether swimming exercise alleviates the depression-like behaviors induced by this paradigm. Pregnant rats received dexamethasone (DEX) (0.1 mg/kg/day) in the last third of pregnancy or vehicle. DEX treatment reduced body weight in 1, 3, 6, 9-week old male offspring, and 3, 6, 9-week old female offspring. DEX treatment resulted in an elevated level of serum corticosterone in adult offspring (9 weeks). Female and male adult offspring rats exhibited decreased number of poking into holes and rearing and decreased central distance traveled in open field test (OFT), and reduced sucrose consumption, suggesting prenatal DEX exposure increase depression-like behaviors in the adult offspring rats. Four-week swimming exercise reduced serum corticosterone levels, and alleviated the depressive behavior by reversing the decreased number of poking into holes and rearing as well as decreased central distance traveled, and reversing the reduced sucrose consumption in male and female adult offspring. These findings suggested prenatal exposure to GCs increase the activity of HPA axis and depression-like behaviors of adult offsprings. Swimming exercise decreases HPA activity and ameliorates depression in rats exposed to DEX prenatally.     

Depression and type 2 diabetes: inflammatory mechanisms of a psychoneuroendocrine co-morbidity

Unipolar depression and diabetes mellitus each account for a significant proportion of the global burden of disease. Epidemiological literature suggests a bi-directional relationship between these two common disorders, and evidence from the molecular sciences supports a role for inflammation in the pathogenesis and pathophysiology of each disorder individually. Recent advances in understanding the neurobiology of depression have implicated dysfunction of the hypothalamus-pituitary-adrenal axis, neurotrophins, and inflammatory mediators in the development of this disorder. Similarly, dysregulated facets of both the innate and adaptive immune system have been implicated in the onset of insulin resistance and type 2 diabetes. This review draws upon an emerging body of epidemiological and mechanistic evidence to support the hypothesis that shared inflammatory mechanisms may represent a key biological link in this co-morbidity. Given the shared mechanisms of this co-morbidity, these patients may be excellent candidates for novel immune targeted pharmacotherapy.     

Central glucocorticoid receptor-mediated effects of the antidepressant, citalopram, in humans: a study using EEG and cognitive testing

Our previous work in cellular and animal models has shown that antidepressants activate glucocorticoid receptor (GR) translocation, induce GR down-regulation, and decrease GR-mediated effects in the presence of GR agonists. However, whether these effects can be extrapolated to the human brain is still unclear. In this study, the effects of four days of treatment with the antidepressant, citalopram (20 mg/day), or placebo, were assessed in a double-blind, placebo-controlled, cross-over study. Central GR-mediated effects were examined by the effects of a single dose of cortisol (30 mg, orally) on two measures known to be sensitive to glucocorticoid administration: EEG alpha power and working memory function. Twenty healthy male subjects aged between 18 and 33 years participated to the study. The results suggest that GR activation by antidepressants, and the subsequent decrease in GR-mediated effects in the presence of GR agonists, indeed occurs in the human brain. Specifically, pre-treatment with citalopram decreased the well-known ability of cortisol to increase EEG alpha power and to impair working memory: cortisol-induced increase in EEG alpha power was (anteriorly) +15 to +20% (p=0.01) after placebo and +5 to +8% (p>0.5) after citalopram; and cortisol-induced increase in working memory errors was (at level 12, on average) 2.50 vs. 4.55 (p<0.05) after placebo and 4.10 vs. 3.35 (p>0.05) after citalopram. No effects were detected on alerting. These results are consistent with the notion that citalopram treatment activates GR translocation and inhibits the functional consequences of the subsequent cortisol administration. Our study further emphasizes the importance of the GR as a target for antidepressant action in humans.     

Inborn differences in environmental reactivity predict divergent diurnal behavioral, endocrine, and gene expression rhythms

Circadian dysfunction has long been implicated in the etiology of mood disorders. The gene Clock and related molecules (e.g. Per1, Per2) represent key regulators of circadian rhythmicity, and their targeted disruption in mutant mice produces potentiated reward drive, novelty-seeking, impulsivity, disrupted sleep, reduced depression and anxiety - a behavioral profile highly reminiscent of our selectively bred high responder (bHR) rats compared to bred low responders (bLRs). The current study evaluated potential diurnal bHR-bLR differences in behavior, gene expression, and neuroendocrinology. Relative to bHRs, bLRs showed diminished homecage locomotion during the dark (but not light) phase and a delayed corticosterone peak. In situ hybridizations in hypothalamus, amygdala, and hippocampus at Zeitgeber Time (ZT)2 and ZT14 revealed distinct bHR-bLR day-night gene expression fluctuations. bHRs exhibited altered day-night patterns of corticotrophin releasing hormone (CRH) and arginine vasopression (AVP) mRNA in the hypothalamus, and perturbed hippocampal MR:GR ratios relative to bLR rats. bHR-bLR rats showed disparate day-night Clock expression in the suprachiasmatic nucleus, a master circadian oscillator, with bHRs showing higher levels at ZT14 versus ZT2 and bLRs showing the opposite pattern. Clock, Per1 and Per2 were assessed in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) since disruption of these genes induces "bHR-like" behavior in mutant mice. Clock and Per1 did not differ between strains, but there were robust Per2 differences, with bHRs having reduced Per2 in VTA and SNc. These findings resonate with earlier work demonstrating that perturbation of Clock and related molecules contributes to disturbances of emotional and addictive behaviors.     

糖皮质激素对急性肺损伤的治疗现状

急性肺损伤(ALI)/成人呼吸窘迫综合征(ARDS)是全身炎性反应综合征在肺部的表现,炎症失控是病变的本质,炎性介质启动了ALI的发生。ALI时常有重症肾上腺皮质功能不全,补充外源性糖皮质激素(GC)可纠正内源性GC的代谢异常,并可通过其受体介导的对多种信号通路的多效性表达,抑制多种细胞因子的转录,减少炎性介质的释放而发挥抗炎、免疫抑制的作用。近年来国内外使用GC治疗ALI的经验表明,"早期使用,中小剂量,延长时间,逐渐减量"的用药方案可望缩短病程,改善患者预后,但其确切的疗效有待于进一步系统研究证实。     

儿童亚急性坏死性淋巴结炎临床分析

目的 探讨亚急性坏死性淋巴结炎(SNL)的病因、临床特征和实验室检查特点,以提高对SNL的认识.方法 回顾性分析14例经病理确诊的SNL患儿的临床资料.结果 发病以学龄儿为主,平均年龄(10.4±2.9)岁,男女之比1.8∶1.临床表现主要为淋巴结肿大、压痛14例(100%),发热13例(92.9%),皮疹、肝脾肿大各2例(14.3%).14例患儿白细胞计数(2.3～7.4)×109/L,平均(3.90±0.35)×109/L,其中白细胞降低10例(71.4%),未见白细胞升高;12例C反应蛋白检测,8例轻度升高(10～30mg/dl);13例患儿行血沉检查,11例(82.6%)高于正常水平(20mm/h),平均40mm/h,最高达70mm/h;8例患儿行抗核抗体检测,2例阳性;12例患儿行抗EB病毒抗体检查4例阳性,11例行血支原体-IgM检查1例阳性,6例行柯萨奇病毒抗体检测1例阳性,柯萨奇、EB病毒混合感染1例;淋巴结组织活检可见大小不一的碎屑状坏死,坏死周围可见组织细胞增生,很少出现浆细胞、嗜中性粒细胞和嗜酸性粒细胞;淋巴结EB病毒DNA检测阴性.8例患儿给予强的松1.5～2.0mg/(kg·d)治疗,效果显著.病情稳定后复查血常规,5例白细胞恢复正常;复发1例,其余患儿预后良好.结论 对于不明原因发热伴淋巴结肿大、疼痛的患儿,应尽早行淋巴结活检确诊,该病呈自限性,糖皮质激素治疗有效,但少数有复发,应长期随访.无证据证明EB病毒在SNL的发病中起作用,白细胞恢复正常可作为病情好转的指标之一.     

豚鼠外周血单个核细胞与耳蜗组织中糖皮质激素体含量的相关性分析

目的通过分析豚鼠外周血单个核细胞(Peripheral blood mononuclear cell,PBMC)与耳蜗组织中糖皮质激素受体(glucocorticoid receptor,GR)mRNA和蛋白含量变化,探讨PBMC与耳蜗组织中GR含量的相关性。方法将32只健康白色豚鼠随机分为地塞米松组和对照组,地塞米松组予地塞米松(5mg/ml,10mg/kg/day)腹腔连续注射7天,对照组予等体积的生理盐水腹腔连续注射7天。给药结束后次日取豚鼠PBMC及双侧耳蜗组织,通过实时荧光定量PCR检测豚鼠PBMC和左耳耳蜗组织中GR mRNA表达水平,通过Western blot结果半定量分析豚鼠PBMC和右侧耳蜗组织中GR蛋白的含量,并运用统计学软件SPSS16.0进一步分析豚鼠PBMC与耳蜗组织中GR mRNA及GR蛋白表达量的相关性及短期全身使用地塞米松对其表达量的影响。结果 GR mRNA与GR蛋白在豚鼠PBMC与耳蜗组织中均有表达,地塞米松组PBMC及耳蜗组织中GR mRNA与GR蛋白含量较对照组有明显提高,统计学相关性分析结果提示地塞米松组及对照组的PBMC与耳蜗组织的GR mRNA、GR蛋白表达量存在正相关,结果有统计学意义。结论豚鼠短期全身使用地塞米松可以使PBMC与耳蜗组织中的GR mRNA、GR蛋白含量均同步上调,豚鼠PBMC与耳蜗组织中GR mRNA、GR蛋白的含量变化具有正相关性。PBMC中GR含量可间接反映耳蜗组织的GR表达水平。