%0 Journal Article
%T Blockade of 4-1BB and 4-1BBL Interaction Reduces Obesity-Induced Skeletal Muscle Inflammation
%A Ngoc Hoan Le
%A Chu-Sook Kim
%A Thai Hien Tu
%A Hye-Sun Choi
%A Byung-Sam Kim
%A Teruo Kawada
%A Tsuyoshi Goto
%A Taesun Park
%A Jung Han Yoon Park
%A Rina Yu
%J Mediators of Inflammation
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/865159
%X 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. 1. Introduction Obesity-induced inflammation, which is commonly observed in major metabolic organs such as adipose tissue, skeletal muscle, and liver, is characterized by increased accumulation of immune cells (macrophages, T cells) and inflammatory cytokine/chemokine production and plays a crucial role in the development of metabolic disorders such as insulin resistance and type 2 diabetes [1, 2]. It is likely that inflammation of skeletal muscle contributes to the diminished fatty acid oxidation and increased insulin resistance [3¨C7], leading to metabolic complications. Given that skeletal muscle, which constitutes up to 40¨C50% of body mass, is a major site regulating lipid and glucose metabolism [8], targeting skeletal muscle inflammatory components may be a useful strategy for protecting against obesity-related metabolic disorders. However, the factors involved in obesity-induced skeletal muscle inflammation remain unclear. 4-1BB (tumor necrosis factor receptor superfamily 9, TNFRSF9) is a costimulatory receptor mainly expressed on the surface of activated T cells and natural killer (NK) T cells [9, 10], while its ligand (4-1BBL, TNFSF9) is expressed on
%U http://www.hindawi.com/journals/mi/2013/865159/