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Mediators of Inflammation
Volume 2013, Article ID 865159, 10 pages
Research Article

Blockade of 4-1BB and 4-1BBL Interaction Reduces Obesity-Induced Skeletal Muscle Inflammation

1Department of Food Science and Nutrition, University of Ulsan, Ulsan 680-749, Republic of Korea
2Department of Biological Science, University of Ulsan, Ulsan 680-749, Republic of Korea
3Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011, Japan
4Department of Food and Nutrition, Yonsei University, Seoul 120-749, Republic of Korea
5Department of Food Science and Nutrition and Research Institute for Bioscience & Biotechnology, Hallym University, Chuncheon 200-702, Republic of Korea

Received 18 June 2013; Revised 12 November 2013; Accepted 20 November 2013

Academic Editor: Jonathan Peake

Copyright © 2013 Ngoc Hoan Le et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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 TNF -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.