Fernandes Pedro A C M, Cecon Erika, Markus Regina P, Ferreira Zulma S
Laboratory of Chronopharmacology, Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.
J Pineal Res. 2006 Nov;41(4):344-50. doi: 10.1111/j.1600-079X.2006.00373.x.
A retino-hypothalamic-sympathetic pathway drives the nocturnal surge of pineal melatonin production that determines the synchronization of pineal function with the environmental light/dark cycle. In many studies, melatonin has been implicated in the modulation of the inflammatory response. However, scant information on the feedback action of molecules present in the blood on the pineal gland during the time course of an inflammatory response is available. Here we analyzed the effect of tumor necrosis factor-alpha (TNF-alpha) and corticosterone on the transcription of the Aa-nat, hiomt and 14-3-3 protein genes in denervated pineal glands of rats stimulated for 5 hr with norepinephrine, using real-time reverse transcription-polymerase chain reaction. The transcription of Aa-nat, a gene encoding the key enzyme in melatonin biosynthesis, together with the synthesis of the melatonin precursor N-acetylserotonin, was inhibited by TNF-alpha. This inhibition was transient, and a preincubation of TNF-alpha for more than 24 hr had no detectable effect. In fact, a protein(s) transcribed, later on, as shown by cycloheximide, was responsible for the reversal of the inhibition of Aa-nat transcription. In addition, corticosterone induced a potentiation of norepinephrine-induced Aa-nat transcription even after 48 hr of incubation. These data support the hypothesis that the nocturnal surge in melatonin is impaired at the beginning of an inflammatory response and restored either during the shutdown of an acute response or in a chronic inflammatory pathology. Here, we introduce a new molecular pathway involved in the feedback of an inflammatory response on pineal activity, and provide a molecular basis for understanding the expression of circadian timing in injured organisms.
一条视网膜-下丘脑-交感神经通路驱动松果体褪黑素分泌的夜间高峰，该高峰决定了松果体功能与环境光/暗周期的同步。在许多研究中，褪黑素被认为参与了炎症反应的调节。然而，关于炎症反应过程中血液中分子对松果体的反馈作用的信息却很少。在此，我们使用实时逆转录-聚合酶链反应，分析了肿瘤坏死因子-α（TNF-α）和皮质酮对用去甲肾上腺素刺激5小时的大鼠去神经松果体中Aa-nat、hiomt和14-3-3蛋白基因转录的影响。编码褪黑素生物合成关键酶的Aa-nat基因的转录以及褪黑素前体N-乙酰血清素的合成受到TNF-α的抑制。这种抑制是短暂的，TNF-α预孵育超过24小时没有可检测到的影响。事实上，如放线菌酮所示，后来转录的一种蛋白质负责逆转Aa-nat转录的抑制。此外，即使在孵育48小时后，皮质酮也能增强去甲肾上腺素诱导的Aa-nat转录。这些数据支持了这样一种假设，即褪黑素的夜间高峰在炎症反应开始时受损，并在急性反应停止期间或慢性炎症病理过程中恢复。在此，我们引入了一条涉及炎症反应对松果体活动反馈的新分子途径，并为理解受伤生物体中昼夜节律的表达提供了分子基础。
