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Mediators Inflamm. 2013;2013:865159. doi: 10.1155/2013/865159. Epub 2013 Dec 18.

Blockade of 4-1BB and 4-1BBL interaction reduces obesity-induced skeletal muscle inflammation.

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


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.

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