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Osteopontin-Activated Human Monocytes Proangiogenic Activity

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Osteopontin-Activated Human Monocytes Proangiogenic Activity Cutting Edge: IL-1β Mediates the Proangiogenic Activity of Osteopontin-Activated Human Monocytes This information is current as Antonella Naldini, Daria Leali, Annalisa Pucci, Emilia of September 28, 2021. Morena, Fabio Carraro, Beatrice Nico, Domenico Ribatti and Marco Presta J Immunol 2006; 177:4267-4270; ; doi: 10.4049/jimmunol.177.7.4267 http://www.jimmunol.org/content/177/7/4267 Downloaded from References This article cites 30 articles, 8 of which you can access for free at: http://www.jimmunol.org/content/177/7/4267.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • 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 by guest on September 28, 2021 *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 © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. THE JOURNAL OF IMMUNOLOGY CUTTING EDGE Cutting Edge: IL-1␤ Mediates the Proangiogenic Activity of Osteopontin-Activated Human Monocytes1 Antonella Naldini,2* Daria Leali,† Annalisa Pucci,* Emilia Morena,* Fabio Carraro,* Beatrice Nico,‡ Domenico Ribatti,‡ and Marco Presta† Inflammation plays an important role in the onset of an- matrix component and as a soluble molecule implicated in in- giogenesis. In the present study, we show that osteopontin flammation, cell-mediated immunity, tissue remodeling, and (OPN), a proinflammatory mediator involved in tissue tumor metastases (8–10). OPN acts as a proinflammatory cy- repair, induces IL-1␤ up-regulation in human mono- tokine that plays important roles in monocyte/macrophage cytes. This was accompanied by the enhanced production functions (11–13). Experiments performed on OPN-null mice of TNF-␣, IL-8, and IL-6, a decreased release of IL-10, implicate OPN in Th1 cell-mediated immunity during infec- Downloaded from and increased p38 phosphorylation. The supernatants of tion, autoimmune demyelinating disease, rheumatoid arthritis, wound healing, and bone resorption (14). OPN-treated monocytes were highly angiogenic when de- In keeping with the tight cross-talk among angiogenic livered on the chick embryo chorioallantoic membrane. growth factors and cytokines, we have shown that OPN up- The angiogenic response was completely abrogated by a regulation in endothelial cells may represent a mechanism of neutralizing anti-IL-1 Ab, thus indicating that this cytokine amplification of growth factor-induced neovascularization http://www.jimmunol.org/ represents the major proangiogenic factor expressed by OPN- (11). The experimental evidence suggests that OPN may affect activated monocytes. Accordingly, rIL-1␤ mimicked the angiogenesis indirectly via mononuclear phagocyte recruitment proangiogenic activity of OPN-treated monocyte superna- and up-regulation of the expression of monocyte-derived tants, and IL-1R (type I) was found to be expressed in the proangiogenic cytokine(s). chorioallantoic membrane. In conclusion, OPN-activated In the present study, we demonstrate that OPN activates a monocytes may contribute to the onset of angiogenesis novel monocyte-mediated mechanism of neovascularization through a mechanism mediated by IL-1␤. The Journal of triggered by IL-1␤. Immunology, 2006, 177: 4267–4270. by guest on September 28, 2021 Materials and Methods he causal relationship between inflammation and an- Reagents giogenesis is now widely accepted (1); however, many Recombinant human OPN, recombinant fibroblast growth factor-2 (FGF-2), ␤ ␣ of the molecular and cellular mechanisms mediating and mAb to IL-1 , IL-8, and TNF- were obtained from R&D Systems. Re- T combinant human IL-1␤ was purchased from Endogen. The serum-free me- this relationship remain unresolved. The term angiogenic dium HYQCCM1 and FBS were obtained from HyClone. Mouse OPN and its switch describes the expression of specific genes that alter the RGD deletion mutant (⌬RGD-OPN) were expressed in Escherichia coli as GST balance between pro- and antiangiogenic molecules that partic- fusion proteins, as described previously (11). Endotoxin levels were always Ͻ0.06 EU/ml (6 pg/ml), as determined by the Limulus amebocyte lysate ipate in blood vessel formation (2). Monocytes/macrophages method (Cambrex). LPS was purchased from Euroclone. produce direct and indirect inducers of angiogenesis, as well as angiogenic inhibitors (3, 4). Also, recent observations have Monocyte preparation and culture shown that IL-1␤ may act as a potent proangiogenic cytokine Human monocytes were obtained from buffy coats of healthy blood donors (5) and that administration of IL-1 receptor antagonist inhibits (through the courtesy of the Blood Center, Siena Medical Center) by Ficoll (Lympholyte-H; Cederlane Laboratories) and Percoll (Amersham Biosciences) tumor growth and neovascularization (6). gradients, as described previously (11). Where indicated, cells were incubated Osteopontin (OPN)3, also known as early T lymphocyte-ac- for 4–24 h with different concentrations of OPN in HYQCCM1 and 1% FBS. tivating gene-1 (7), is a phosphorylated acidic RGD-containing Then, conditioned medium (CM) was collected and evaluated either for cyto- kine content or for its angiogenic activity in the gelatin sponge/chick embryo glycoprotein that binds certain CD44 variants and integrin re- chorioallantoic membrane (CAM) assay. In parallel, monocytes were lysed, and ceptors (8). OPN exists both as an immobilized extracellular total RNA was extracted for quantitative RT-PCR (qRT-PCR) analysis. *Unit of Neuroimmunophysiology, Department of Physiology, University of Siena, Siena, G. Berlucchi, Istituto Superiore Sanita`(Progetto Oncotecnologico), and Associazione Italy; †Unit of General Pathology and Immunology, Department of Biomedical Sciences Italiana per la Ricerca sul Cancro (Italy) (to M.P.). and Biotechnology, University of Brescia, Brescia, Italy; and ‡Department of Human 2 Address correspondence and reprint requests to Dr. Antonella Naldini, Unit of Neu- Anatomy and Histology, University of Bari, Bari, Italy roimmunophysiology, Department of Physiology, University of Siena, Via Aldo Received for publication April 6, 2006. Accepted for publication July 26, 2006. Moro, 53100 Siena, Italy. E-mail address: [email protected] The costs of publication of this article were defrayed in part by the payment of page charges. 3 Abbreviations used in this paper: OPN, osteopontin; FGF-2, fibroblast growth fac- This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. tor-2; CM, conditioned medium; CAM, chorioallantoic membrane; qRT-PCR, quan- Section 1734 solely to indicate this fact. titative RT-PCR; RGD, Arg-Gly-Asp. 1 This work was supported by grants from MIUR (Cofin 2004) and Fondazione MPS (to A.N.) and from MIUR (Centro di Eccellenza IDET, FIRB 2001, Cofin 2004), Fondazione Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 4268 CUTTING EDGE: IL-1␤ AND OPN INTERACTION IN ANGIOGENESIS Measurement of cytokines by ELISA IL-1␤, TNF-␣, IL-6, IL-8, and IL-10 concentrations were assessed on mono- cytes supernatants by ELISA using high-performance ELISA reagents (Euro- clone). None of the assays showed cross-reactivity with other cytokines. The minimum detectable doses were for IL-1␤, TNF-␣, IL-6, and IL-10 Ͻ 5 pg/ml and for IL-8 Ͻ 25 pg/ml. RT-PCR and qRT-PCR IL-1RI mRNA expression in control unstimulated CAM was analyzed by RT- PCR. Total RNA was extracted from CAM fragments using the TRIzol Re- agent (Invitrogen Life Technologies). RNA samples (2 ␮g) were retrotrans- cribed with Ready-To-Go You-Prime First Strand Beads (Amersham Biosciences). PCR were performed on cDNA samples using the forward primer, 5Ј-TGCCATCTTGATCCTCAATG-3Ј, and the reverse primer, 5Ј- TGGAAGCAAGCCATACACAC-3Ј (chicken IL-1RI: GenBank accession no. NM_205485). Amplified products were subjected to electrophoresis on agarose gel and visualized by ethidium bromide staining. IL-1␤ mRNA expression in OPN-treated monocytes was determined by qRT-PCR using a MJ MiniOpticon Cycler (Bio-Rad). Total RNA was isolated using RNAwiz (Ambion). First-strand cDNA synthesis was performed using a iScript cDNA Synthesis kit (Bio-Rad). qRT-PCR was performed using iTaq SYBR Green Supermix with ROX (Bio-Rad) and the following primers: IL-1␤ Downloaded from forward, 5Ј-TGATGGCTTATTACAGTGGCAATG-3Ј, and IL-1␤ reverse, 5Ј-GTAGTGGTGGTGGGAGATTCG-3Ј; and ␤-actin forward, 5Ј-CGC FIGURE 1. OPN induces a proinflammatory response in human mono- CGCCAGCTCACCATG-3Ј, and ␤-actin reverse, 5Ј-CACGATGGAGGG cytes. A, OPN induces p38-MAPK activation in human monocytes. Human GAAGACGG-3Ј (GenBank accession no. for IL-1␤, NM000576, and for monocytes were treated with 100 nM OPN at different time points, and ␤ -actin, NM001101). Data were quantitatively analyzed on an MJ Opticon- cellular extracts were probed with anti-phospho-p38 Ab and an anti-pan- Monitor detection system (Bio-Rad). All values were expressed as fold increase ␤ p38 Ab, as a loading control. B–F,
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