Valdés-Tovar Marcela, Escobar Carolina, Solís-Chagoyán Héctor, Asai Miguel, Benítez-King Gloria
Laboratorio de Neurofarmacología, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz , Tlalpan, Distrito Federal , México .
Chronobiol Int. 2015 Mar;32(2):164-77. doi: 10.3109/07420528.2014.960047. Epub 2014 Sep 23.
The light-dark cycle is an environmental factor that influences immune physiology, and so, variations of the photoperiod length result in altered immune responsivity. Macrophage physiology comprises a spectrum of functions that goes from host defense to immune down-regulation, in addition to their homeostatic activities. Macrophages also play a key role in the transition from innate to adaptive immune responses. Met-enkephalin (MEnk) has been recognized as a modulator of macrophage physiology acting in an autocrine or paracrine fashion to influence macrophage activation, phenotype polarization and production of cytokines that would enhance lymphocyte activation at early stages of an immune response. Previously it was shown that splenic MEnk tissue content is reduced in rats exposed to constant light. In this work, we explored whether production of Met-enkephalin-containing peptides (MECPs) in cultured splenic macrophages is affected by exposure of rats to a constant light regime. In addition, we explored whether primary immune response was impaired under this condition. We found that in rats, 15 days in constant light was sufficient to disrupt their general activity rhythm. Splenic MEnk content oscillations and levels were also blunted throughout a 24-h period in animals subjected to constant light. In agreement, de novo synthesis of MECPs evaluated through incorporation of (35)S-methionine was reduced in splenic macrophages from rats exposed to constant light. Moreover, MECPs immunocytochemistry showed a decrease in the intracellular content and lack of granule-like deposits in this condition. Furthermore, we found that primary T-dependent antibody response was compromised in rats exposed to constant light. In those animals, pharmacologic treatment with MEnk increased IFN-γ-secreting cells. Also, IL-2 secretion from antigen-stimulated splenocytes was reduced after incubation with naloxone, suggesting that immune-derived opioid peptides and stimulation of opioid receptors are involved in this process. Thus, the immune impairment observed from early stages of the response in constant light-subjected rats, could be associated with reduced production of macrophage-derived enkephalins, leading to a sub-optimal interaction between macrophages and lymphocytes in the spleen and the subsequent deficiency in antibody production.
明暗周期是一种影响免疫生理学的环境因素，因此，光周期长度的变化会导致免疫反应性改变。巨噬细胞生理学包括一系列功能，除了其稳态活动外，还涵盖从宿主防御到免疫下调的过程。巨噬细胞在从先天免疫反应向适应性免疫反应的转变中也起着关键作用。甲硫氨酸脑啡肽（MEnk）已被公认为巨噬细胞生理学的调节剂，以自分泌或旁分泌方式发挥作用，影响巨噬细胞的激活、表型极化以及细胞因子的产生，而这些细胞因子会在免疫反应的早期阶段增强淋巴细胞的激活。此前研究表明，暴露于持续光照的大鼠脾脏中甲硫氨酸脑啡肽的组织含量会降低。在这项研究中，我们探究了培养的脾脏巨噬细胞中含甲硫氨酸脑啡肽的肽（MECPs）的产生是否会受到大鼠暴露于持续光照条件的影响。此外，我们还探究了在此条件下初次免疫反应是否受损。我们发现，在大鼠中，持续光照15天足以扰乱其一般活动节律。在持续光照的动物中，脾脏中甲硫氨酸脑啡肽含量的振荡和水平在整个24小时周期内也变得平缓。与此一致的是，通过掺入（35）S-甲硫氨酸评估的MECPs的从头合成在暴露于持续光照的大鼠的脾脏巨噬细胞中减少。此外，MECPs免疫细胞化学显示在此条件下细胞内含量减少且缺乏颗粒样沉积物。此外，我们发现暴露于持续光照的大鼠的初次T细胞依赖性抗体反应受到损害。在这些动物中，用甲硫氨酸脑啡肽进行药物治疗可增加分泌干扰素-γ的细胞。同样，用纳洛酮孵育后，抗原刺激的脾细胞分泌白细胞介素-2减少，这表明免疫衍生的阿片肽和阿片受体的刺激参与了这一过程。因此，在持续光照的大鼠中从反应早期观察到的免疫损伤可能与巨噬细胞衍生的脑啡肽产生减少有关，导致脾脏中巨噬细胞与淋巴细胞之间的相互作用不理想，以及随后抗体产生不足。
