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ONLINE LETTERS TO THE EDITOR Response to Comment on: Kim et al. Deficiency for Costimulatory Receptor 4-1BB Protects Against Obesity-Induced Inflammation and Metabolic Disorders. Diabetes 2011;60:3159–3168 Rina Yu I thank Drs. Gomez-Mejiba and Ramirez for their letter (1) and for initiating further discussion of possible mechanisms underlying the effects of 4-1BB stimulation/deficiency on the obesity-induced responses of T cells/macrophages in adipose tissue (2,3), and how both conditions can lead to protection against metabolic complications. Obesity-induced adipose inflammation is currently considered to create an optimal environment for autoimmune effects to take root (4). 4-1BB stimulation with agonistic anti–4-1BB antibody is known to attenuate many autoimmune inflammatory diseases by enhancing the expansion of regulatory T cells (Tregs) and hyperactivating g-interferon (IFN-g)–producing CD81 Tregs (5). Our observations that IFN-g (IFN-g itself directly inhibits monocyte migration [6]) and interleukin (IL)-10 increase in response to 4-1BB stimulation (2) suggest that the anti–4-1BB antibody–induced Tregs suppress the obesity-induced pathogenic responses of inflammatory cells (Th1, CD81 T cells, M1 macrophages) in a manner similar to the way they control autoimmune diseases, and this may ultimately lead to protection against metabolic disorders. Alternatively, it has become clear that the interaction of 4-1BB with 4-1BB ligand (4-1BBL) regulates various inflammatory processes in a bidirectional manner (7,8), and this often complicates the interpretation of experiments using agonistic anti–4-1BB antibody and/or 4-1BB deletion models (8). Macrophages express 4-1BBL, and 4-1BBL–mediated reverse signaling on macrophages promotes their proliferation and survival and causes them to release cytokines (8). Intriguingly, it is likely that agonistic anti–4-1BB antibody blocks the 4-1BBL–mediated inflammatory responses of 4-1BBL– expressing cells by disturbing the 4-1BB/4-1BBL interaction (9). Hence, 4-1BBL–mediated reverse signaling in adipose macrophages may be suppressed in conditions of both 4-1BB stimulation and deficiency, leading in each case to protecting obesity-induced inflammation and metabolic complications (2,3). As discussed previously (2,3), 4-1BB stimulation/deficiency differentially alters cellular responses of immune cells and enhances lipid/glucose metabolism. We suppose that there may be a relationship between 4-1BB/ 4-1BBL signaling and metabolic pathways, and this possibility is currently under investigation in our laboratory. Elucidation of the mechanisms underlying the effects of 4-1BB/4-1BBL signals on immunometabolism may provide clues to the link between inflammation and metabolism. ACKNOWLEDGMENTS No potential conflicts of interest relevant to this article were reported. REFERENCES 1. Gomez-Mejiba SE, Ramirez DC. Comment on: Kim et al. Deficiency for costimulatory receptor 4-1BB protects against obesity-induced inflammation and metabolic disorders. Diabetes 2011;60:3159–3168 (Letter). Diabetes 2012; 61:e6. DOI: 10.2337/db12-0128 2. Kim C-S, Tu TH, Kawada T, Kim B-S, Yu R. The immune signaling molecule 4-1BB stimulation reduces adiposity, insulin resistance, and hepatosteatosis in obese mice. Endocrinology 2010;151:4725–4735 3. Kim C-S, Kim JG, Lee B-J, et al. Deficiency for costimulatory receptor 4-1BB protects against obesity-induced inflammation and metabolic disorders. Diabetes 2011;60:3159–3168 4. Matarese G, Procaccini C, De Rosa V, Horvath TL, La Cava A. Regulatory T cells in obesity: the leptin connection. Trends Mol Med 2010;16:247– 256 5. Seo SK, Choi JH, Kim YH, et al. 4-1BB-mediated immunotherapy of rheumatoid arthritis. Nat Med 2004;10:1088–1094 6. Hu Y, Hu X, Boumsell L, Ivashkiv LB. IFN-gamma and STAT1 arrest monocyte migration and modulate RAC/CDC42 pathways. J Immunol 2008; 180:8057–8065 7. Wang C, Lin GH, McPherson AJ, Watts TH. Immune regulation by 4-1BB and 4-1BBL: complexities and challenges. Immunol Rev 2009;229:192– 215 8. Shao Z, Schwarz H. CD137 ligand, a member of the tumor necrosis factor family, regulates immune responses via reverse signal transduction. J Leukoc Biol 2011;89:21–29 9. Kim HJ, Lee JS, Kim JD, et al. Reverse signaling through the costimulatory ligand CD137L in epithelial cells is essential for natural killer cell-mediated acute tissue inflammation. Proc Natl Acad Sci USA 2012;109:E13–E22 From the Department of Food Science and Nutrition, University of Ulsan, Ulsan, South Korea. Corresponding author: Rina Yu, [email protected]. DOI: 10.2337/db12-0356 Ó 2012 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details. diabetes.diabetesjournals.org DIABETES, VOL. 61, JULY 2012 e7