Ruzicka B B, Akil H
Mental Health Research Institute, University of Michigan, Ann Arbor 48109-0720, U.S.A.
Neuroscience. 1997 Jul;79(2):517-24. doi: 10.1016/s0306-4522(96)00669-0.
Opioids have been found to modulate the function of the immune system by regulating the biochemical and proliferative properties of its cellular components. The interaction of opioid and immune systems, however, is not unidirectional, but rather, bidirectional in nature. In the CNS, one cellular target of immune system activation is the astrocytes, glial cells known to synthesize proenkephalin. We have recently shown that these cells also express the messenger RNA transcripts for the opioid receptors mu, delta and kappa, raising the question of the functional significance of this opioid peptide and the related receptors in the astrocytes. That is, why do astrocytes express proenkephalin and opioid receptors, and are these molecules responsive to a factor to which the astrocytes could be exposed in vivo? Furthermore, do these molecules respond to this factor in a region-specific fashion? In the present study, in order to characterize the astrocytic opioid response to an immune factor, we examined the concomitant regulation of mu, delta, kappa and proenkephalin messenger RNAs by interleukin-1beta (1 ng/ml=60 pM, 24 h) in primary astrocyte-enriched cultures derived from the rat (post-natal day 1-2) cortex, striatum, cerebellum, hippocampus and hypothalamus. Interleukin-1beta treatment was found to increase by 55-75% the level of mu receptor messenger RNA in striatal, cerebellar and hippocampal cultures, but not in cultures derived from the cortex or hypothalamus. However, the cytokine had no effect on the level of delta receptor messenger RNA in any of the five cultures examined. In marked contrast to its stimulatory effects on mu receptor messenger RNA levels and its lack of an effect on 6 receptor messenger RNA expression, interleukin-1beta reduced to 10-30% of control levels the kappa receptor messenger RNA levels in all cultures. Interleukin-1beta had no effect on the level of proenkephalin messenger RNA in cortical, striatal, cerebellar and hypothalamic cultures, but did significantly decrease the expression of proenkephalin messenger RNA in hippocampal cultures to 40% of the control level. Therefore, interleukin-1beta differentially regulated opioid receptor messenger RNA in astrocyte-enriched cultures in a manner dependent upon both the receptor type and the brain region from which the culture was derived. The cytokine also differentially regulated proenkephalin messenger RNA in a region-dependent fashion. These findings suggest a capacity for astrocytes to differentially regulate opioid peptide and receptor messenger RNAs in response to an immune factor, supporting the potential existence of a novel immune-opioid system interaction in the CNS.
已发现阿片类药物可通过调节其细胞成分的生化和增殖特性来调节免疫系统的功能。然而，阿片类药物与免疫系统的相互作用并非单向的，而是具有双向性。在中枢神经系统中，免疫系统激活的一个细胞靶点是星形胶质细胞，这是一种已知能合成前脑啡肽原的神经胶质细胞。我们最近发现，这些细胞还表达阿片受体μ、δ和κ的信使核糖核酸转录本，这就提出了这种阿片肽及其相关受体在星形胶质细胞中的功能意义问题。也就是说，为什么星形胶质细胞会表达前脑啡肽原和阿片受体，这些分子是否对星形胶质细胞在体内可能接触到的一种因子有反应？此外，这些分子是否以区域特异性方式对这种因子作出反应？在本研究中，为了表征星形胶质细胞对免疫因子的阿片反应，我们检测了白细胞介素-1β（1纳克/毫升 = 60皮摩尔，24小时）对源自大鼠（出生后第1 - 2天）皮质、纹状体、小脑、海马体和下丘脑的原代星形胶质细胞富集培养物中μ、δ、κ和前脑啡肽原信使核糖核酸的协同调节作用。发现白细胞介素-1β处理可使纹状体、小脑和海马体培养物中μ受体信使核糖核酸水平提高55 - 至75%，但对源自皮质或下丘脑的培养物没有影响。然而，该细胞因子对所检测的五种培养物中的δ受体信使核糖核酸水平均无影响。与它对μ受体信使核糖核酸水平的刺激作用及其对δ受体信使核糖核酸表达无影响形成鲜明对比的是，白细胞介素-1β使所有培养物中的κ受体信使核糖核酸水平降至对照水平的10 - 30%。白细胞介素-1β对皮质、纹状体、小脑和下丘脑培养物中的前脑啡肽原信使核糖核酸水平没有影响，但确实使海马体培养物中的前脑啡肽原信使核糖核酸表达显著降低至对照水平的40%。因此，白细胞介素-1β以一种既依赖于受体类型又依赖于培养物所源自的脑区的方式，对星形胶质细胞富集培养物中的阿片受体信使核糖核酸进行差异调节。该细胞因子还以区域依赖的方式对前脑啡肽原信使核糖核酸进行差异调节。这些发现表明星形胶质细胞有能力响应免疫因子对阿片肽和受体信使核糖核酸进行差异调节，支持中枢神经系统中存在一种新型免疫 - 阿片系统相互作用的可能性。
