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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–
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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
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