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Adipocytes As Immune Cells: Differential Expression of TWEAK

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Adipocytes As Immune Cells: Differential Expression of TWEAK Adipocytes as Immune Cells: Differential Expression of TWEAK, BAFF, and APRIL and Their Receptors (Fn14, BAFF-R, TACI, and BCMA) at Different Stages of Normal This information is current as and Pathological Adipose Tissue of September 26, 2021. Development Vassilia-Ismini Alexaki, George Notas, Vassiliki Pelekanou, Marilena Kampa, Maria Valkanou, Panayiotis Theodoropoulos, Efstathios N. Stathopoulos, Andreas Tsapis Downloaded from and Elias Castanas J Immunol published online 14 October 2009 http://www.jimmunol.org/content/early/2009/10/14/jimmuno l.0901186 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2009/10/13/jimmunol.090118 Material 6.DC1 Why The JI? Submit online. by guest on September 26, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2009 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published October 14, 2009, doi:10.4049/jimmunol.0901186 The Journal of Immunology Adipocytes as Immune Cells: Differential Expression of TWEAK, BAFF, and APRIL and Their Receptors (Fn14, BAFF-R, TACI, and BCMA) at Different Stages of Normal and Pathological Adipose Tissue Development1 Vassilia-Ismini Alexaki,* George Notas,* Vassiliki Pelekanou,2* Marilena Kampa,* Maria Valkanou,* Panayiotis Theodoropoulos,† Efstathios N. Stathopoulos,‡ Andreas Tsapis,3§ and Elias Castanas3* Adipose tissue represents a rich source of multipotent stem cells. Mesenchymal cells, isolated from this source, can differentiate to other cell types in vitro and therefore can be used for a number of regenerative therapies. Our view of adipose tissue has recently Downloaded from changed, establishing adipocytes as new members of the immune system, as they produce a number of proinflammatory cytokines (such as IL-6 and TNF␣ and chemokines, in addition to adipokines (leptin, adiponectin, resistin) and molecules associated with the innate immune system. In this paper, we report the differential expression of TNF-superfamily members B cell activating factor of the TNF Family (BAFF), a proliferation inducing ligand (APRIL), and TNF-like weak inducer of apoptosis (TWEAK) in immature-appearing and mature adipocytes and in benign and malignant adipose tissue-derived tumors. These ligands act through their cognitive receptors, BAFF receptor, transmembrane activator and calcium signal-modulating cyclophilic ligand http://www.jimmunol.org/ (TACI), B cell maturation Ag (BCMA), and fibroblast growth factor-inducible 14 (Fn14), which are also expressed in these cells. We further report the existence of functional BCMA, TACI, and Fn14 receptors and their ligands BAFF, APRIL, and TWEAK on adipose tissue-derived mesenchymal cells, their interaction modifying the rate of adipogenesis. Our data integrate BAFF, APRIL, and TWEAK and their receptors BCMA, TACI, and Fn14 as novel potential mediators of adipogenesis, in addition to their specific role in immunity, and define immature and mature adipocytes as source of immune mediators. The Journal of Immunology, 2009, 183: 5948–5956. lthough adipose tissue has long been regarded as an al- The TNF superfamily is a group of receptors and ligands con- by guest on September 26, 2021 most inert tissue, dedicated solely to energy storage and sisting of 19 ligands and 29 receptors. They orchestrate a wide A release, recent data dramatically changed our opinion. range of biological functions, from the regulation of activation and Indeed, recent insights into the metabolic and immunological func- cell death in the immune system to tissue homeostasis and cancer tions of preadipocytes and adipocytes revealed that they are potent cell modulation (3). Among the different members of this family, producers of proinflammatory cytokines (such as IL-6 and TNF-␣) an increased interest has been shown recently for the subset of B and chemokines, regulating monocyte/macrophage function (1) cell activating factor of the TNF Family (BAFF),4 a proliferation and molecules associated with the innate immune system, such as inducing ligand (APRIL), and TNF-like weak inducer of apoptosis the C1q/TNF-related superfamily. Finally, preadipocytes and adi- (TWEAK). APRIL (CD256, TNF-SF13) (4–6) and BAFF pocytes express a broad spectrum of functional Toll-like receptors (CD257, TNF-SF13B) (6–9) have been identified as trophic fac- and can convert into macrophage-like cells (reviewed in Ref. 2). tors in lymphocyte malignancies and immune-related disorders These data clearly establish adipose tissue as a new player in im- (10). APRIL and BAFF have also been identified in a number of mune reactions. immune-related and immune-independent tissues (spleen, liver, lung, heart, intestine, kidney, and thymus) (11). They both bind to † *Department of Experimental Endocrinology, Department of Biochemistry, and two TNF-R family members, transmembrane activator and cal- ‡Department of Pathology, University of Crete, School of Medicine, Heraklion, Greece; and §UMR976 INSERM, Hoˆpital St Louis, Paris, France cium signal-modulating cyclophilic ligand (TACI) (TNFRSF13B) Received for publication April 14, 2009. Accepted for publication September 3, 2009. and B cell maturation Ag (BCMA) (TNFRSF17) (12, reviewed in The costs of publication of this article were defrayed in part by the payment of page Ref. 13). APRIL binds also syndecan-1 (CD138), a heparan sulfate charges. This article must therefore be hereby marked advertisement in accordance proteoglycan present on the surface of many cell types (14, 15), with 18 U.S.C. Section 1734 solely to indicate this fact. allowing ligand polymerization and cross-linking (14–17). BAFF 1 This work was supported by grants from INSERM and the University of Crete Research Committee. 2 Current address: Laboratoire J.-C. Heuson de Cance´rologie Mammaire, Institut Ju- les Bordet-Centre des Tumeurs de l’ULB, Brussels, 1000, Belgium. 3 Address correspondence and reprint requests to Dr. Elias Castanas, University of 4 Abbreviations used in this paper: BAFF, B cell activating factor of the TNF family; Crete, School of Medicine, Laboratory of Experimental Endocrinology, P.O. Box APRIL, a proliferation inducing ligand; TWEAK, TNF-like weak inducer of apopto- 2208, Heraklion, 71003, Greece. E-mail address: [email protected] or Dr. An- sis; TACI, transmembrane activator and calcium signal-modulating cytophilic ligand; dreas Tsapis, UMR976 INSERM, Hoˆpital St Louis, 1, Av. Claude Vellefaux, Paris, BCMA, B cell maturation Ag; BAFF-R, BAFF receptor; Fn14, fibroblast growth 75010, France. E-mail address: [email protected] factor-inducible 14; LPL, lipoprotein lipase; ADMC, adipose tissue-derived mesen- chymal cell; MSC, mesenchymal stem cell; qRT-PCR, quantitative RT-PCR; SF, Copyright © 2009 by The American Association of Immunologists, Inc. 0022-1767/09/$2.00 Superfamily. www.jimmunol.org/cgi/doi/10.4049/jimmunol.0901186 The Journal of Immunology 5949 specifically binds to another TNF-R family member, BAFF-recep- Immunohistochemistry tor (BAFF-R) (TNFRSF13C) (18). Binding to these receptors trig- After deparaffinization and hydration, slides were subjected to three 5-min gers diverse signaling pathways, including translocation of NF␬B cycles of citrate buffer (0.01M, pH 6.0) incubation in a 500-W microwave or activation of mitogen-activated kinases (19, reviewed in Ref. oven and treated with 3% hydrogen peroxide for 15 min, as appropriate. 20). They were incubated for 30 min with primary Abs to APRIL (hAprily-8 TWEAK/Fn14 represents another ligand/receptor couple, also mouse mAb, 1/100 dilution, ALX-804–149, Alexis Biochemicals), BAFF (ALX-804–131 mAb/Buffy-2 clone, dilution 1/100, Alexis Biochemicals), mediating pluripotent responses. First described as a TNF-like TWEAK (sc-12405, 1/100 dilution, Santa Cruz Biotechnology), BCMA weak inducer of apoptosis, TWEAK (TNF-SF12) has since (Vicky-1 rat mAb, 1/100 dilution, ALX-804–151, Alexis Biochemicals), emerged as a cytokine, regulating multiple cellular responses, in- TACI (IMG-249 rabbit polyclonal Ab, 1/150 dilution, Imgenex), BAFF-R cluding proinflammatory activity, angiogenesis, cellular prolifera- (goat polyclonal, AF1162, dilution 1/100, R&D Systems), or Fn14 (mouse monoclonal, sc-56250, dilution 1/50, Santa Cruz Biotechnology). The tion, differentiation, and migratory capacity, suggesting a potential UltraVision LP Detection System (TL-060-AL, Lab Vision) with Fast Red, role in inflammation and cancer (reviewed in Ref. 21). TWEAK is the HRP detection kit (BD Biotechnologies) or the K0689 LSAB kits highly expressed by inflammatory cells, expressed as a type II- (DakoCytomation) were used for immunodetection, as appropriate. Coun- transmembrane protein that can be cleaved to function as a soluble terstaining was performed using Mayer’s hematoxylin. Known positive and cytokine (22). It acts through its cognitive receptor, fibroblast negative controls (omission
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