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

• Published in: Mediators of Inflammation 2013-01, Vol.2013 (2013), p.90-99
• Main Authors: Le, Ngoc Hoan, Kim, Chu-Sook, Tu, Thai Hien, Choi, Hye-Sun, Kim, Byung-Sam, Kawada, Teruo, Goto, Tsuyoshi, Park, Taesun, Yoon Park, Jung Han, Yu, Rina
• Format: Article
• Language: English
• Subjects: 4-1BB Ligand - antagonists & inhibitors; 4-1BB Ligand - genetics; 4-1BB Ligand - physiology; Animals; Cells, Cultured; Complications and side effects; Health aspects; Inflammation; Inflammation - etiology; Inflammation - prevention & control; Mice; Mice, Inbred C57BL; Muscle, Skeletal - pathology; Muscles; Obesity; Obesity - complications; Physiological aspects; RNA, Messenger - analysis; Tumor necrosis factor; Tumor Necrosis Factor Receptor Superfamily, Member 9 - antagonists & inhibitors; Tumor Necrosis Factor Receptor Superfamily, Member 9 - genetics; Tumor Necrosis Factor Receptor Superfamily, Member 9 - physiology
• ISSN: 0962-9351; 1466-1861
• DOI: 10.1155/2013/865159

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.