Schraml Elisabeth, Fuchs Robert, Kotzbeck Petra, Grillari Johannes, Schauenstein Konrad
Institute of Pathophysiology and Immunology, Center of Molecular Medicine, Medical University of Graz, Graz, Austria.
Stem Cells Dev. 2009 Mar;18(2):215-27. doi: 10.1089/scd.2008.0072.
Acute adrenergic stress is a cause of hematopoietic failure that accompanies severe injury. Although the communication between neuronal and immune system is well documented and catecholamines are known as important regulators of homeostasis, the molecular mechanisms of hematopoietic failure are not well understood. To study the influence of adrenergic stress on hematopoietic progenitor cells (HPCs), which recently have been found to express adrenergic receptors, Lin(-),Sca(+), cells were isolated and treated with alpha- and beta-adrenergic agonists in vitro. Indeed, this stimulation resulted in significantly decreased colony formation capacity using granulocyte/macrophage colony-forming unit assays. This decline was dependent on the formation of reactive oxygen species (ROS) and activation of the p38/mitogen-activated protein kinase (MAPK) pathway, since the addition of antioxidants or a p38 inhibitor restored CFU formation. DNA damage by adrenergically induced ROS, however, does not seem to account for the reduction of colonies. Thus, catecholamine/p38/MAPK is identified as a key signal transduction pathway in HPCs besides those dependent on Wnt, Notch, and sonic hedgehog. Furthermore, a well-known target of p38 signaling, p16 is transcriptionally activated after adrenergic stimulation, suggesting that cell cycle arrest might importantly contribute to hematopoietic failure and immune dysfunctions after severe injury. Since increased levels of catecholamines are also observed in other conditions, such as during aging which is linked with decline of immune functions, adrenergic stress might as well contribute to the lowered immune defence in the elderly.
急性肾上腺素能应激是严重损伤所伴随的造血功能衰竭的一个原因。尽管神经元与免疫系统之间的通讯已有充分记载，且儿茶酚胺是已知的内环境稳态的重要调节因子，但造血功能衰竭的分子机制尚未完全明确。为了研究肾上腺素能应激对造血祖细胞（HPCs）的影响，最近发现这些细胞表达肾上腺素能受体，于是分离出Lin(-)、Sca(+)细胞并在体外使用α和β肾上腺素能激动剂进行处理。事实上，通过粒细胞/巨噬细胞集落形成单位试验，这种刺激导致集落形成能力显著下降。这种下降依赖于活性氧（ROS）的形成和p38/丝裂原活化蛋白激酶（MAPK）途径的激活，因为添加抗氧化剂或p38抑制剂可恢复CFU形成。然而，肾上腺素能诱导的ROS造成的DNA损伤似乎并不能解释集落数量的减少。因此，除了依赖Wnt、Notch和音猬因子的信号转导途径外儿茶酚胺/p38/MAPK被确定为HPCs中的关键信号转导途径。此外，p38信号的一个已知靶点p16在肾上腺素能刺激后被转录激活，这表明细胞周期停滞可能对严重损伤后的造血功能衰竭和免疫功能障碍起重要作用。由于在其他情况下也观察到儿茶酚胺水平升高，比如在与免疫功能下降相关的衰老过程中，肾上腺素能应激也可能导致老年人免疫防御能力降低。
