Departament de Ciències Fisiològiques, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, C/Feixa Llarga, s/n 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
Departament de Nefrologia, Hospital Universitari de Bellvitge, IDIBELL, Barcelona, Spain.
Mol Cell Biochem. 2018 Nov;448(1-2):187-197. doi: 10.1007/s11010-018-3325-9. Epub 2018 Feb 12.
Lymphocyte activation is associated with rapid increase of both the glycolytic activator fructose 2,6-bisphosphate (Fru-2,6-P) and the enzyme responsible for its synthesis, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2). PFKFB3 gene, which encodes for the most abundant PFK-2 isoenzyme in proliferating tissues, has been found overexpressed during cell activation in several models, including immune cells. However, there is limited knowledge on the pathways underlying PFKFB3 regulation in human T-lymphocytes, and the role of this gene in human immune response. The aim of this work is to elucidate the molecular mechanisms of PFKFB3 induction during human T-lymphocyte activation by mitotic agents. The results obtained showed PFKFB3 induction during human T-lymphocyte activation by mitogens such as phytohemagglutinin (PHA). PFKFB3 increase occurred concomitantly with GLUT-1, HK-II, and PCNA upregulation, showing that mitotic agents induce a metabolic reprograming process that is required for T-cell proliferation. PI3K-Akt pathway inhibitors, Akti-1/2 and LY294002, reduced PFKFB3 gene induction by PHA, as well as Fru-2,6-P and lactate production. Moreover, both inhibitors blocked activation and proliferation in response to PHA, showing the importance of PI3K/Akt signaling pathway in the antigen response of T-lymphocytes. These results provide a link between metabolism and T-cell antigen receptor signaling in human lymphocyte biology that can help to better understand the importance of modulating both pathways to target complex diseases involving the activation of the immune system.
淋巴细胞的激活伴随着糖酵解激活剂果糖 2,6-二磷酸（Fru-2,6-P）和负责其合成的酶，6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶（PFK-2/FBPase-2）的迅速增加。PFKFB3 基因编码增殖组织中最丰富的 PFK-2 同工酶，在包括免疫细胞在内的几种模型中，细胞激活时发现其过度表达。然而，关于人 T 淋巴细胞中 PFKFB3 调节的途径知之甚少，以及该基因在人类免疫反应中的作用。本工作旨在阐明有丝分裂剂诱导人 T 淋巴细胞中 PFKFB3 诱导的分子机制。研究结果表明，丝裂原如植物血球凝集素（PHA）可诱导人 T 淋巴细胞激活时的 PFKFB3 诱导。PFKFB3 的增加与 GLUT-1、HK-II 和 PCNA 的上调同时发生，表明有丝分裂剂诱导了 T 细胞增殖所需的代谢重编程过程。PI3K-Akt 通路抑制剂 Akti-1/2 和 LY294002 降低了 PHA 诱导的 PFKFB3 基因诱导，以及 Fru-2,6-P 和乳酸的产生。此外，两种抑制剂均阻断了对 PHA 的激活和增殖反应，表明 PI3K/Akt 信号通路在 T 淋巴细胞对抗原的反应中很重要。这些结果在人类淋巴细胞生物学中提供了代谢与 T 细胞抗原受体信号之间的联系，有助于更好地理解调节这两条途径以靶向涉及免疫系统激活的复杂疾病的重要性。
