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Endothelial Cells Markers Prox-1 and Podoplanin in Human IL-3 Induces

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Endothelial Cells Markers Prox-1 and Podoplanin in Human IL-3 Induces IL-3 Induces Expression of Lymphatic Markers Prox-1 and Podoplanin in Human Endothelial Cells This information is current as Marion Gröger, Robert Loewe, Wolfgang Holnthoner, of September 25, 2021. Robert Embacher, Manuela Pillinger, G. Scott Herron, Klaus Wolff and Peter Petzelbauer J Immunol 2004; 173:7161-7169; ; doi: 10.4049/jimmunol.173.12.7161 http://www.jimmunol.org/content/173/12/7161 Downloaded from References This article cites 54 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/173/12/7161.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 25, 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 © 2004 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology IL-3 Induces Expression of Lymphatic Markers Prox-1 and Podoplanin in Human Endothelial Cells1 Marion Gro¨ger,*† Robert Loewe,* Wolfgang Holnthoner,* Robert Embacher,*† Manuela Pillinger,*† G. Scott Herron,‡ Klaus Wolff,*† and Peter Petzelbauer2*† Factors determining lymphatic differentiation in the adult organism are not yet well characterized. We have made the observation that mixed primary cultures of dermal blood endothelial cells (BEC) and lymphatic endothelial cells (LEC) grown under standard conditions change expression of markers during subculture: After passage 6, they uniformly express LEC-specific markers Prox-1 and podoplanin. Using sorted cells, we show that LEC but not BEC constitutively express IL-3, which regulates Prox-1 and podoplanin expression in LEC. The addition of IL-3 to the medium of BEC cultures induces Prox-1 and podoplanin. Blocking IL-3 activity in LEC cultures results in a loss of Prox-1 and podoplanin expression. In conclusion, endogenous IL-3 is required to maintain the LEC phenotype in culture, and the addition of IL-3 to BEC appears to induce transdifferentiation of BEC into Downloaded from LEC. The Journal of Immunology, 2004, 173: 7161–7169. nterleukin-3 is a broadly acting regulatory protein of hemo- tively expressed markers are N-cadherin (22–24), pathologische poietic cell differentiation. It stimulates proliferation, sur- anatomie Leiden-endothelium Ag (PAL-E) (for microvessels) (16, I vival, and differentiation of pluripotent hemopoietic stem 25), or CXCR4 (22, 23). During embryogenesis, factors governing cells, and promotes expansion of cells that differentiate into mature lymphatic differentiation are well described. The transcription fac- http://www.jimmunol.org/ cell lineages. Interestingly, IL-3 also has the capacity to divert tor Prox-1 is the earliest detectable marker of lymphatic differen- differentiation of already committed cells. In the presence of IL-3, tiation and is essential for differentiation of lymphatic EC (LEC) cells of the osteoclast lineage differentiate into cells of the mac- from the anterior cardinal vein endothelium (14, 26, 27). Lym- rophage lineage (1). IL-3 signals to cells via the IL-3R, which is phangiogenesis is regulated by growth factors VEGF-C and composed of an IL-3-specific ␣-chain and a common ␤-chain VEGF-D and their receptor VEGFR-3 (20, 28–30). The trans- shared with the GM-CSFR ␣-chain and the IL-5R ␣-chain (2, 3). membrane mucoprotein podoplanin was shown to be important for Endothelial cells (EC)3 express IL-3R ␣- and ␤-chains, and ex- the correct lymphatic network formation (26). In the adult organ- pression can be increased by stimulation with TNF-␣ and/or IFN-␥ ism, the situation is more complex and less defined. For example, (4). EC respond to IL-3 by expressing IL-8 and E-selectin (5, 6). in some tumors and in inflammation, the lymphatic growth factor by guest on September 25, 2021 Moreover, IL-3 promotes endothelial tube formation and direc- receptor VEGFR-3 is expressed on proliferating lymphatic and tional migration (7). Cultured EC have been identified as a source blood vessels, resulting in VEGF-C-induced lymph and blood ves- of IL-3 (8). Whether EC-derived IL-3 has autocrine functions is sel formation (31–34). This raises the question whether additional unknown, as is the question of a role for IL-3 in EC differentiation. factors exist, which determine differentiation of LEC within the EC invest two distinct vascular trees, one building the transport adult organism. In this study, we demonstrate that IL-3 regulates system for blood and the other for lymph. They differ by morphol- expression of LEC-specific markers Prox-1 and podoplanin. ogy and phenotype as reviewed recently by several authors (9–13). Established markers for human lymphatic cells are, for example, Materials and Methods Prox-1 (14), podoplanin (15, 16) (also called T1␣ (17) or gp36 Cells (18)), vascular endothelial growth factor (VEGF)R-3 (19, 20), and lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) HUVEC were isolated as described (35) and cultured in IMDM with 20% (21). Also for blood EC (BEC), lineage-specific genes have been FCS, glutamine (2 mM; Invitrogen Life Technologies, Carlsbad, CA), pen- icillin (100 U/ml), streptomycin (100 ␮g/ml; both Invitrogen Life Tech- identified by transcriptional profiling (22–24), among constitu- nologies), and heparin/ECGS (PromoCell, Heidelberg, Germany). Foreskin-derived microvascular EC were isolated and cultured as de- scribed (36). Briefly, foreskins were treated with dispase (Invitrogen Life *Department of Dermatology, Division of General Dermatology, Medical University of Vienna, and †Ludwig Boltzmann Institute for Angiogenesis, Microcirculation and Technologies) for 20 min at 37°C, followed by mechanically scraping EC Inflammation, Vienna, Austria; and ‡Department Dermatology, Palo Alto Medical with a cell scraper. Cells were then seeded into fibronectin-coated wells Clinic, Palo Alto, CA 94301 and cultured in EC growth medium (MV/ECGS; PromoCell). At passage 1, BEC and LEC were separated by magnetic sorting with an anti-podoplanin Received for publication May 26, 2004. Accepted for publication October 4, 2004. serum (15, 16). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Antibodies 1 This work was supported by a research grant from the Stavros Niarchos Foundation. First step Abs were as follows: anti-Prox-1 (RDI, Flanders, NJ), anti- 2 Address correspondence and reprint requests to Dr. Peter Petzelbauer, Depart- macrophage mannose receptor (BD Pharmingen, San Jose, CA), PAL-E ment of Dermatology, Division of General Dermatology, Medical University of (RDI), anti-N-cadherin (BD Pharmingen), FITC-labeled CD31 (Immuno- Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. E-mail address: tech, Marseille, France), anti-IL-3R ␣-chain Ab for FACS (clone 9F5), and [email protected] blocking anti-IL-3R ␣-chain Ab (clone 7G3; both BD Pharmingen). As a 3 Abbreviations used in this paper: EC, endothelial cell; BEC, blood EC; LEC, lymphatic specificity control for the anti-podoplanin serum, we raised a mouse mono- EC; VEGF, vascular endothelial growth factor; LYVE, lymphatic vessel endothelial clonal anti-human podoplanin Ab using peptide GASTGQPEDDTETT hyaluronan receptor; PAL-E, pathologische anatomie Leiden-endothelium Ag. GLEGG (aa 22–40) as the Ag; a rabbit anti-human podoplanin serum was Copyright © 2004 by The American Association of Immunologists, Inc. 0022-1767/04/$02.00 7162 IL-3 INDUCES Prox-1 AND PODOPLANIN a gift from Dr. D. Kerjaschki (Department of Pathology, Medical Univer- cells. As a positive control, we used CD31 Abs, which reacted sity of Vienna). Isotype controls were purchased from Sigma-Aldrich (St. equally with LEC and BEC (Fig. 1B). Louis, MO). Second step Abs were as follows: tetramethylrhodamine iso- thiocyanate-labeled goat anti-rabbit F(ab)2 (Jackson ImmunoResearch IL-3 is constitutively expressed in LEC Laboratories, West Grove, PA). PE-labeled goat anti-rabbit F(ab)2 (BD Pharmingen), Alexa 488-labeled anti-rabbit IgG (Molecular Probes, Lei- The molecular characterization of sorted LEC and BEC is shown den, The Netherlands), FITC-labeled anti-mouse-IgG (Sigma-Aldrich), and in Fig. 1C. LEC are characterized by the expression of podoplanin, HRP-labeled anti-mouse or anti-rabbit IgG (Bio-Rad, Hercules, CA). Flt-4, LYVE-1, Prox-1, and mannose receptor, and BEC by PAL-E FACS and laser scan analysis and N-cadherin expression. To determine factors inducing podo- planin expression of mixed (nonsorted) LEC/BEC in culture, we For FACS, cells were detached from culture dishes using trypsin/EDTA. screened cell culture supernatants of sorted LEC and BEC for cy- For laser scan imaging, cells were directly fixed on culture dishes with acetone/methanol (1:1) at Ϫ20°C for 10 min. Samples were then incubated tokines. We found IL-3 consistently present in LEC and absent in with indicated first-step Abs followed by the appropriate fluorescence-la- BEC supernatants (Fig. 2A). HUVEC were analyzed for compar- beled second-step Abs. Isotype-matched control Abs were used in parallel. ison and also found negative for IL-3 (see also Nilsen et al. (8)). Bound fluorescence was analyzed by FACScan (BD Biosciences, Moun- Primary cultures, which, due to the isolation procedure, consisted tain View, CA) or laser scan microscope (LSM 520; Zeiss, Oberkochen, of a mixture of LEC and BEC (mixed LEC/BEC), had slightly Germany).
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