title: 4-1BBL signaling promotes cell proliferation through reprogramming of glucose metabolism in monocytes/macrophages.
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.
authors.affiliation: Department of Food Science and Nutrition, University of Ulsan, South Korea.
authors.forename: Thai H
authors.initials: TH
authors.lastname: Tu
authors.forename: Chu-Sook
authors.initials: CS
authors.lastname: Kim
authors.forename: Il S
authors.initials: IS
authors.lastname: Nam-Goong
authors.forename: Chang W
authors.initials: CW
authors.lastname: Nam
authors.forename: Young-Il
authors.initials: YI
authors.lastname: Kim
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Goto
authors.forename: Teruo
authors.initials: T
authors.lastname: Kawada
authors.forename: Taesun
authors.initials: T
authors.lastname: Park
authors.forename: Jung H
authors.initials: JH
authors.lastname: Yoon Park
authors.forename: Zae Y
authors.initials: ZY
authors.lastname: Ryoo
authors.forename: Jeong W
authors.initials: JW
authors.lastname: Park
authors.forename: Hye-Seon
authors.initials: HS
authors.lastname: Choi
authors.forename: Rina
authors.initials: R
authors.lastname: Yu
mesh_terms: D053330:4-1BB Ligand / Q000235:genetics / Q000378:metabolism*; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007333:Insulin Resistance; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D053330:4-1BB Ligand; D016207:Cytokines; D012333:RNA, Messenger; D005947:Glucose
keywords: inflammation; macrophage; metabolic reprogramming; obesity; proliferation