OBJECTIVE Circadian rhythms are generated by the suprachiasmatic nucleus of the hypothalamus and involve rhythmic expression of clock genes and proteins. This rhythmicity is transferred to peripheral tissues by neural and hormonal signals. Late pregnancy is considered a state of inflammation which impacts on peripheral tissues such as joints. Tumor necrosis factor (TNF) mediates inflammatory and circadian responses through its p55 receptor (TNFRp55). Neuroimmunoendocrine interactions in joints have not been studied completely. The purpose of this study was to analyze these interactions, investigating the circadian rhythms of progesterone (Pg) and pro- and anti-inflammatory cytokines in the joints at the end of pregnancy (gestational day 18). Moreover, the impact of TNFRp55 deficiency on these temporal oscillations was explored. METHODS Wild-type and TNFRp55-deficient (KO) C57BL/6 mice were kept under constant darkness in order to study their endogenous circadian rhythms. The expression of the clock genes Bmal1 and Per1 at circadian time 7 was studied by reverse transcription polymerase chain reaction in the ankle joints of nonpregnant and pregnant (gestational day 18) mice. In late pregnancy, Pg and the cytokines interleukin 17 (IL-17), IL-6, and IL-10 were measured in the joints throughout a 24-h period by radioimmunoassay and enzyme-linked immunosorbent assay, respectively. RESULTS A significant increase in Bmal1 and Per1 mRNA expression was detected in the joints of pregnant KO mice. Furthermore, KO mice displayed a desynchronization of articular Pg and cytokine production. CONCLUSIONS Our results show that TNF, via TNFRp55 signaling, modulates articular Pg and cytokine circadian rhythms in late pregnancy. These findings suggest a temporal neuroimmunoendocrine association in peripheral tissues in late pregnancy.

中文翻译：

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周围神经免疫内分泌相互作用：TNFRp55对晚期妊娠小鼠关节中孕酮的昼夜同步和细胞因子产生的贡献。

目的昼夜节律是由下丘脑的视交叉上核产生的，涉及时钟基因和蛋白质的节律性表达。这种节律性通过神经和激素信号传递到周围组织。怀孕后期被认为是一种炎症状态，会影响周围组织，例如关节。肿瘤坏死因子（TNF）通过其p55受体（TNFRp55）介导炎症和昼夜节律反应。尚未完全研究关节中的神经免疫内分泌相互作用。这项研究的目的是分析这些相互作用，研究孕晚期（妊娠第18天）关节中孕酮（Pg）的昼夜节律以及促炎和抗炎细胞因子的变化。此外，探索了TNFRp55缺乏对这些时间振荡的影响。方法将野生型和TNFRp55缺陷型（KO）C57BL / 6小鼠置于持续黑暗中，以研究其内源性昼夜节律。通过逆转录聚合酶链反应在未怀孕和怀孕（妊娠第18天）小鼠的踝关节中研究了昼夜节律时间7的时钟基因Bmal1和Per1的表达。在妊娠晚期，通过放射免疫测定和酶联免疫吸附测定分别在整个24小时内测量关节中的Pg和细胞因子白介素17（IL-17），IL-6和IL-10。结果在怀孕的KO小鼠关节中检测到Bmal1和Per1 mRNA表达显着增加。此外，KO小鼠显示出关节Pg和细胞因子产生的失步。结论我们的结果表明TNF通过TNFRp55信号传导 在妊娠后期调节关节Pg和细胞因子的昼夜节律。这些发现提示妊娠晚期外周组织中存在暂时性神经免疫内分泌关联。