Institutes of Biophysics, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil.
Institutes of Microbiology, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil.
J Biol Chem. 2012 Oct 12;287(42):35506-35515. doi: 10.1074/jbc.M112.394924. Epub 2012 Aug 21.
The prion protein (PrP(C)) is a cell surface protein expressed mainly in the nervous system. In addition to the role of its abnormal conformer in transmissible spongiform encephalopathies, normal PrP(C) may be implicated in other degenerative conditions often associated with inflammation. PrP(C) is also present in cells of hematopoietic origin, including T cells, dendritic cells, and macrophages, and it has been shown to modulate their functions. Here, we investigated the impact of inflammation and stress on the expression and function of PrP(C) in neutrophils, a cell type critically involved in both acute and chronic inflammation. We found that systemic injection of LPS induced transcription and translation of PrP(C) in mouse neutrophils. Up-regulation of PrP(C) was dependent on the serum content of TGF-β and glucocorticoids (GC), which, in turn, are contingent on the activation of the hypothalamic-pituitary-adrenal axis in response to systemic inflammation. GC and TGF-β, either alone or in combination, directly up-regulated PrP(C) in neutrophils, and accordingly, the blockade of GC receptors in vivo curtailed the LPS-induced increase in the content of PrP(C). Moreover, GC also mediated up-regulation of PrP(C) in neutrophils following noninflammatory restraint stress. Finally, neutrophils with up-regulated PrP(C) presented enhanced peroxide-dependent cytotoxicity to endothelial cells. The data demonstrate a novel interplay of the nervous, endocrine, and immune systems upon both the expression and function of PrP(C) in neutrophils, which may have a broad impact upon the physiology and pathology of various organs and systems.
朊病毒蛋白（PrP(C)）是一种主要在神经系统中表达的细胞表面蛋白。除了其异常构象在传染性海绵状脑病中的作用外，正常的 PrP(C) 可能与其他常伴有炎症的退行性疾病有关。PrP(C)也存在于造血细胞中，包括 T 细胞、树突状细胞和巨噬细胞，并且已经表明它可以调节它们的功能。在这里，我们研究了炎症和应激对中性粒细胞中 PrP(C)表达和功能的影响，中性粒细胞是急性和慢性炎症中都至关重要的细胞类型。我们发现，全身注射 LPS 可诱导小鼠中性粒细胞中转录和翻译 PrP(C)。PrP(C)的上调依赖于 TGF-β 和糖皮质激素（GC）的血清含量，而这又取决于下丘脑-垂体-肾上腺轴对全身炎症的反应。GC 和 TGF-β 单独或联合直接上调中性粒细胞中的 PrP(C)，并且体内 GC 受体的阻断可减少 LPS 诱导的 PrP(C)含量增加。此外，非炎症性束缚应激后，GC 也介导了中性粒细胞中 PrP(C)的上调。上调 PrP(C)的中性粒细胞对内皮细胞的过氧化物依赖性细胞毒性增强。这些数据表明，在中性粒细胞中 PrP(C)的表达和功能方面，神经系统、内分泌系统和免疫系统之间存在一种新的相互作用，这可能对各种器官和系统的生理学和病理学产生广泛影响。
