Antigen receptor-mediated changes in glucose metabolism in B lymphocytes: role of phosphatidylinositol 3-kinase signaling in the glycolytic control of growth
Antigen receptor-mediated changes in glucose metabolism in B lymphocytes: role of phosphatidylinositol 3-kinase signaling in the glycolytic control of growth
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DOI：
10.1182/blood-2005-12-4788
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发表时间：
2006-06-01
期刊：
影响因子：
20.3
通讯作者：
Chiles, Thomas C.
中科院分区：
文献类型：
--
作者：
Doughty, Cheryl A.;Bleiman, Blair F.;Chiles, Thomas C.
B淋巴细胞的生物能反应在抗原接触后发生快速变化，以提供支持生长所需的ATP和合成代谢前体。然而，参与葡萄糖获取和代谢的途径是未知的。我们发现B淋巴细胞在B细胞抗原受体（BCR）交联后迅速增加葡萄糖摄取和糖酵解。糖酵解的抑制阻断BCR介导的生长。在进入S期之前，葡萄糖代谢从主要的糖酵解转变为包括戊糖磷酸途径。BCR诱导的葡萄糖利用依赖于磷脂酰肌醇3-激酶（PI-3 K）活性，如通过LY 294002处理正常B细胞抑制葡萄糖摄取和糖酵解以及PI-3 K调节亚基p85 α缺陷的B细胞葡萄糖利用受损所证明。Akt的活化足以增加B细胞中的葡萄糖利用。我们发现BCR和Fc γ RIIB的共同参与抑制了葡萄糖的利用，这表明限制葡萄糖代谢可能是Fc γ RIIB介导的生长停滞的重要机制。综上所述，这些发现表明生长促进BCR信号传导和生长抑制Fc γ RIIB信号传导均调节葡萄糖能量代谢。这些途径的操作可证明可用于治疗淋巴组织增生性疾病，其中B淋巴细胞的克隆扩增起作用。
The bioenergetic response of B lymphocytes is subject to rapid changes following antigen encounter in order to provide ATP and anabolic precursors necessary to support growth. However, the pathways involved in glucose acquisition and metabolism are unknown. We find that B lymphocytes rapidly increase glucose uptake and glycolysis following B-cell antigen receptor (BCR) crosslinking. Inhibition of glycolysis blocks BCR-mediated growth. Prior to S-phase entry, glucose metabolism shifts from primarily glycolytic to include the pentose phosphate pathway. BCR-induced glucose utilization is dependent upon phosphatidylinositol 3-kinase (PI-3K) activity as evidenced by inhibition of glucose uptake and glycolysis with LY294002 treatment of normal B cells and impaired glucose utilization in B cells deficient in the PI-3K regulatory subunit p85 alpha. Activation of Akt is sufficient to increase glucose utilization in B cells. We find that glucose utilization is inhibited by coengagement of the BCR and Fc gamma RIIB, suggesting that limiting glucose metabolism may represent an important mechanism underlying Fc gamma RIIB-mediated growth arrest. Taken together, these findings demonstrate that both growth-promoting BCR signaling and growth-inhibitory Fc gamma RIIB signaling modulate glucose energy metabolism. Manipulation of these pathways may prove to be useful in the treatment of lymphoproliferative disorders, wherein clonal expansion of B lymphocytes plays a role.