Blockade of 4-1BB and 4-1BBL interaction reduces obesity-induced skeletal muscle inflammation.
Obesity-induced skeletal muscle inflammation is characterized by increased macrophage infiltration and inflammatory cytokine production. In this study, we investigated whether 4-1BB, a member of the TNF receptor superfamily (TNFRSF9) that provides inflammatory signals, participates in obesity-induced skeletal muscle inflammation. Expression of the 4-1BB gene, accompanied by increased levels of inflammatory cytokines, was markedly upregulated in the skeletal muscle of obese mice fed a high-fat diet, in muscle cells treated with obesity factors, and in cocultured muscle cells/macrophages. In vitro stimulation of 4-1BB with agonistic antibody increased inflammatory cytokine levels in TNFα-pretreated muscle cells, and this effect was absent in cells derived from 4-1BB-deficient mice. Conversely, disruption of the interaction between 4-1BB and its ligand (4-1BBL) with blocking antibody decreased the release of inflammatory cytokines from cocultured muscle cells/macrophages. Moreover, deficiency of 4-1BB markedly reduced macrophage infiltration and inflammatory cytokine production in the skeletal muscle of mice fed a high-fat diet. These findings indicate that 4-1BB mediates the inflammatory responses in obese skeletal muscle by interacting with its ligand 4-1BBL on macrophages. Therefore, 4-1BB and 4-1BBL may be useful targets for prevention of obesity-induced inflammation in skeletal muscle.
Department of Food Science and Nutrition, University of Ulsan, Ulsan 680-749, Republic of Korea.
Ngoc Hoan
NH
Le
Department of Food Science and Nutrition, University of Ulsan, Ulsan 680-749, Republic of Korea.
Chu-Sook
CS
Kim
Department of Food Science and Nutrition, University of Ulsan, Ulsan 680-749, Republic of Korea.
Thai Hien
TH
Tu
Department of Biological Science, University of Ulsan, Ulsan 680-749, Republic of Korea.
Hye-Sun
HS
Choi
Department of Biological Science, University of Ulsan, Ulsan 680-749, Republic of Korea.
Byung-Sam
BS
Kim
Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011, Japan.
Teruo
T
Kawada
Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011, Japan.
Tsuyoshi
T
Goto
Department of Food and Nutrition, Yonsei University, Seoul 120-749, Republic of Korea.
Taesun
T
Park
Department of Food Science and Nutrition and Research Institute for Bioscience & Biotechnology, Hallym University, Chuncheon 200-702, Republic of Korea.
Jung Han Yoon
JH
Park
Department of Food Science and Nutrition, University of Ulsan, Ulsan 680-749, Republic of Korea.
Rina
R
Yu
D053330:4-1BB Ligand / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D007249:Inflammation / Q000209:etiology* / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000473:pathology*; D009765:Obesity / Q000150:complications*; D012333:RNA, Messenger / Q000032:analysis; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
D053330:4-1BB Ligand; D012333:RNA, Messenger; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9