4-1BBL signaling promotes cell proliferation through reprogramming of glucose metabolism in monocytes/macrophages

Thai H. Tu, Chu Sook Kim, Il S. Nam-Goong, Chang W. Nam, Young Il Kim, Tsuyoshi Goto, Teruo Kawada, Taesun Park, Jung H. Yoon Park, Zae Y. Ryoo, Jeong W. Park, Hye Seon Choi, Rina Yu

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8 Citations (Scopus)

Abstract

Obesity-induced monocyte/macrophage proliferation and activation play a crucial role in various chronic inflammatory metabolic disorders, such as insulin resistance, diabetes mellitus, and atherosclerosis. 4-1BBL, a member of the tumor necrosis factor superfamily expressed on monocytes/macrophages, provides inflammatory signals to modulate their proliferation, survival, and cytokine release. Previously, we demonstrated that 4-1BBL signaling promotes adipose inflammation through enhancement of macrophage activation. Here, we show that 4-1BBL stimulation on monocytes/macrophages enhanced reprogramming of glucose metabolism in the cells, and that this was accompanied by cell proliferation. 4-1BBL stimulation on macrophages increased glucose uptake, transcript/protein levels of glucose transporter 1 and glycolytic enzymes, and lactate production. It also enhanced transcript levels of genes involved in the pentose phosphate pathway and lipogenesis. The 4-1BBL-induced metabolic reprogramming was mediated by AKT-mammalian target of rapamycin signaling. The effect of 4-1BBL-induced macrophage proliferation was completely abolished by 2-deoxyglucose, a glycolytic inhibitor. These findings suggest that 4-1BBL signaling promotes cell proliferation through reprogramming of glucose metabolism in monocytes/macrophages to support their energy demands and biomass production. The 4-1BBL signaling pathway may be a valid target for controlling macrophage-mediated chronic inflammation in obesity and metabolic diseases.

Original languageEnglish
Pages (from-to)1468-1480
Number of pages13
JournalFEBS Journal
Volume282
Issue number8
DOIs
Publication statusPublished - 2015 Apr 1

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Tu, T. H., Kim, C. S., Nam-Goong, I. S., Nam, C. W., Kim, Y. I., Goto, T., Kawada, T., Park, T., Yoon Park, J. H., Ryoo, Z. Y., Park, J. W., Choi, H. S., & Yu, R. (2015). 4-1BBL signaling promotes cell proliferation through reprogramming of glucose metabolism in monocytes/macrophages. FEBS Journal, 282(8), 1468-1480. https://doi.org/10.1111/febs.13236