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Endothelial Cells Microvascular Secretion from Human Dermal Eotaxin/CCL11 Suppresses IL-8/CXCL8 Secretion from Human Dermal Microvascular Endothelial Cells This information is current as Sara S. Cheng, Nicholas W. Lukacs and Steven L. Kunkel of October 2, 2021. J Immunol 2002; 168:2887-2894; ; doi: 10.4049/jimmunol.168.6.2887 http://www.jimmunol.org/content/168/6/2887 Downloaded from References This article cites 60 articles, 27 of which you can access for free at: http://www.jimmunol.org/content/168/6/2887.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • 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 by guest on October 2, 2021 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 © 2002 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Eotaxin/CCL11 Suppresses IL-8/CXCL8 Secretion from Human Dermal Microvascular Endothelial Cells1 Sara S. Cheng,* Nicholas W. Lukacs,† and Steven L. Kunkel2*† The CC chemokine eotaxin/CCL11 is known to bind to the receptor CCR3 on eosinophils and Th2-type lymphocytes. In this study, we demonstrate that CCR3 is expressed on a subpopulation of primary human dermal microvascular endothelial cells and is up-regulated by TNF-␣. We found that incubation of human dermal microvascular endothelial cells with recombinant eotaxin/ CCL11 suppresses TNF-␣-induced production of the neutrophil-specific chemokine IL-8/CXCL8. The eotaxin/CCL11-suppressive effect on endothelial cells was not seen on IL-1␤-induced IL-8/CXCL8 release. Eotaxin/CCL11 showed no effect on TNF-␣-induced up-regulation of growth-related oncogene-␣ or IFN-␥-inducible protein-10, two other CXC chemokines tested, and did not affect production of the CC chemokines monocyte chemoattractant protein-1/CCL2 and RANTES/CCL5, or the adhesion molecules ICAM-1 and E-selectin. These results suggest that eotaxin/CXCL11 is not effecting a general suppression of TNF-␣R levels or signal transduction. Suppression of IL-8/CXCL8 was abrogated in the presence of anti-CCR3 mAb, pertussis toxin, and wort- Downloaded from mannin, indicating it was mediated by the CCR3 receptor, Gi proteins, and phosphatidylinositol 3-kinase signaling. Eotaxin/ CCL11 decreased steady state levels of IL-8/CXCL8 mRNA in TNF-␣-stimulated cells, an effect mediated in part by an accel- eration of IL-8 mRNA decay. Eotaxin/CCL11 may down-regulate production of the neutrophil chemoattractant IL-8/CXCL8 by endothelial cells in vivo, acting as a negative regulator of neutrophil recruitment. This may play an important biological role in the prevention of overzealous inflammatory responses, aiding in the resolution of acute inflammation or transition from neutro- philic to mononuclear/eosinophilic inflammation. The Journal of Immunology, 2002, 168: 2887–2894. http://www.jimmunol.org/ hemokines are a large family of small, basic peptides that eases possessing an eosinophilic component, such as allergic have mainly been characterized as leukocyte chemoat- asthma (20, 21), chronic sinusitis (22), and allergic rhinitis (23), C tractants. They are divided into four subfamilies based on and is thought to be a key player in the pathogenesis of these the number and spacing of conserved cysteines within the amino conditions. In addition, eotaxin/CCL11 mRNA is up-regulated in terminus of each peptide, with each subfamily having a limited the lesions of patients with inflammatory bowel disease (24) and specificity for different leukocyte subsets. Chemokines from the within lymphomas from patients with Hodgkin’s disease (25), sug- CXC family, in which the first two conserved cysteines are sepa- gesting that eotaxin/CCL11 may play a role in these diseases as well. rated by a nonconserved amino acid, are chemoattractants for poly- Early reports characterizing the tissue expression patterns of by guest on October 2, 2021 morphonuclear phagocytes, some T lymphocyte subsets, and NK eotaxin/CCL11 in human, guinea pig, and mouse tissues demon- cells (1). Members of the CC family, in which the cysteines are strate that eotaxin/CCL11 mRNA is constitutively expressed in a adjacent to one another, have a broader spectrum of action that wide array of tissues, including the gut mucosa, lung, heart, testes, includes monocytes, eosinophils, basophils, NK cells, and T lym- and endometrium (15, 26–28). Relatively few chemokines are ex- phocytes (2). Lymphotactin/XCL1 and fractalkine/CX3CL1 are pressed in a constitutive fashion. The constitutive expression of the sole members of the C and CX3C families, respectively. Lym- eotaxin/CCL11 in a wide variety of tissues, often in the absence of photactin is chemotactic for T lymphocytes (3), while fractalkine a significant eosinophil infiltrate, suggests that it may play a role in acts on both lymphoid cells and neutrophils (4). While chemokines maintaining homeostasis in these tissues. Eotaxin/CCL11 exerts its are widely recognized as important chemotactic factors, some of chemotactic activity primarily through the chemokine receptor these proteins have other varied functions, including immunoregu- CCR3, a seven-transmembrane receptor coupled to heterotrimeric lation (5–7), lymphocyte activation (8, 9), embryonic development G proteins. The CCR3 has been found on human brain endothelial (10, 11), and angiogenesis (12–14). cells (29, 30), and recent studies indicate it may be involved in Eotaxin/CCL11 is a member of the CC chemokine family that angiogenesis (31). To further study CCR3 function in endothelial has potent chemotactic activity for eosinophils (15, 16), basophils cells in vitro, we investigated whether primary cultures of endothelial (17), mast cells (18), and Th2-type lymphocytes (19). Eotaxin/ cells express CCR3, and we uncovered a novel regulatory role for eotaxin and CCR3 on endothelial cell chemokine production. CCL11 protein is up-regulated in a variety of inflammatory dis- Materials and Methods *Graduate Program in Cellular and Molecular Biology and †Department of Pathology, Cytokines and other reagents University of Michigan Medical Center, Ann Arbor, MI 48109 Recombinant human IL-1␤, TNF-␣, eotaxin/CCL11, RANTES/CCL5, and Received for publication September 21, 2001. Accepted for publication January monocyte chemoattractant protein-1 (MCP-1)3/CCL2 were purchased from 7, 2002. R&D Systems (Minneapolis, MN). Abs against E-selectin, ICAM-1, IL- The costs of publication of this article were defrayed in part by the payment of page 8/CXCL8, MCP-1/CCL2, RANTES/CCL5, and CCR3 were purchased charges. This article must therefore be hereby marked advertisement in accordance from R&D Systems. Actinomycin D, pertussis toxin, and wortmannin with 18 U.S.C. Section 1734 solely to indicate this fact. were purchased from Sigma-Aldrich (St. Louis, MO) and stored at a 1 This work was supported by National Institutes of Health Grants HL35276 (to S.L.K.), NIGMS T32GM0786 (to S.S.C.), and GM07315 (to S.S.C.). 2 Address correspondence and reprint requests to Dr. Steven L. Kunkel, Department 3 Abbreviations used in this paper: MCP-1, monocyte chemoattractant protein-1; of Pathology, University of Michigan Medical Center, 1301 Catherine Street, Ann Gro␣, growth-related oncogene-␣; HDMEC, human dermal microvascular endothe- Arbor, MI 48109-0602. E-mail address: [email protected] lial cell; IP-10, IFN-␥-inducible protein-10; PI3K, phosphatidylinositol 3-kinase. Copyright © 2002 by The American Association of Immunologists 0022-1767/02/$02.00 2888 EOTAXIN REGULATES IL-8 PRODUCTION IN ECs concentration of 2.5 mg/ml, 100 ng/␮l, and 10 mM, respectively, in ICAM-1 expression occurred after 24 h. At appropriate time points, culture DMSO at Ϫ20°C. medium was removed and the adherent monolayers were washed three times with 200 ␮l PBS containing Ca2ϩ/Mg2ϩ and 0.1% BSA (PBS/BSA). Cell culture A total of 100 ␮l saturating concentration of biotinylated primary Ab Human dermal microvascular endothelial cells (HDMEC) were obtained in against E-selectin, ICAM-1, or goat IgG (diluted in endothelial cell growth medium) was added. Plates were incubated for 45 min at 37°C. Primary Ab single donor ampules from Clonetics. Cells were passaged by trypsiniza- ␮ ␮ tion and seeding at 1 ϫ 105 cells/ml in endothelial cell growth medium-2 was removed by washing twice with 200 l PBS/BSA. A total of 100 l (Clonetics, Walkersville, MD) medium on plates or flasks (Costar, Corn- 1/5000 dilution of streptavidin-HRP (BD PharMingen) diluted in PBS/ BSA was added, and plates were incubated for 30 min at 37°C. Plates were ing, NY) coated with 2% gelatin (Sigma-Aldrich). Cells were used at pas- ␮ ␮ sages 2–6 for all experiments. washed twice with 200 l PBS/BSA, and 100 l o-phenylenediamine sub- strate (DAKO, Glostup, Denmark) was added to wells. Plates were allowed RNase protection assay to develop at room temperature for 2–20 min. Fifty microliters of 3 M sulfuric acid were added to stop reaction, and chromophore development Total RNA was isolated using TRIzol reagent (Life Technologies, Rock- was determined by measuring OD490 using microplate reader. OD readings ville, MD), according to manufacturer’s instructions, and used in the stan- from samples stained with goat IgG were consistently indistinguishable dard BD PharMingen (San Diego, CA) RNase protection protocol, as fol- from readings taken from unstained samples, indicating no nonspecific lows. The multiprobe template sets hCR5 (containing DNA templates for binding of the Ab was occurring. CCR1, CCR3, CCR4, CCR5, CCR8, CCR2aϩb, CCR2a, CCR2b, L32, and GAPDH) and hCR6 (containing DNA templates for CXCR1, CXCR2, RNA isolation and cDNA synthesis CXCR3, CXCR4, CXCR5, CX3CR1, L32, and GAPDH) were purchased from BD PharMingen.
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