{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T23:02:44Z","timestamp":1791154964174,"version":"4.1.0"},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2009,7,1]],"date-time":"2009-07-01T00:00:00Z","timestamp":1246406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The CC chemokine CCL14a is constitutively expressed in a large variety of tissues and its inactive proform CCL14a(1\u201374) circulates in high concentrations in plasma. CCL14a(1\u201374) is converted into CCL14a(9\u201374) by the proteases urokinase-type plasminogen activator and plasmin and is a highly active agonist for the chemokine receptors CCR1 and CCR5. In this study, a new CCL14a analog, CCL14a(12\u201374), was isolated from blood filtrate. To elucidate the functional role of the N terminus, a panel of N-terminally truncated CCL14a analogs were tested on the receptors CCR1 to CCR5 and on the human cytomegalovirus (HCMV)-encoded chemokine receptor US28. The rank order of binding affinity to these receptors and of the activation of CCR1 and CCR5-mediated intracellular Ca2+ concentration mobilization is CCL14a(6\u201374)&amp;lt;(7\u201374)&amp;lt;(8\u201374)\u226a(9\u201374) = (10\u201374)\u226b(11\u201374)\u226b(12\u201374). The almost identical affinities of CCL14a(7\u201374), CCL14a(9\u201374), and CCL14a(10\u201374) for the US28 receptor and the inhibition of US28-mediated HIV infection of 293T cells by all of the N-terminally truncated CCL14a analogs support the promiscuous nature of the viral chemokine receptor US28. In high concentrations, CCL14a(12\u201374) did reveal antagonistic activity on intracellular Ca2+ concentration mobilization in CCR1- and CCR5-transfected cells, which suggests that truncation of Tyr11 might be of significance for an efficient inactivation of CCL14a. A putative inactivation pathway of CCL14a(9\u201374) to CCL14a(12\u201374) may involve the dipeptidase CD26\/dipeptidyl peptidase IV (DPPIV), which generates CCL14a(11\u201374), and the metalloprotease aminopeptidase N (CD13), which displays the capacity to generate CCL14a(12\u201374) from CCL14a(11\u201374). Our results suggest that the activity of CCL14a might be regulated by stringent proteolytic activation and inactivation steps.<\/jats:p>","DOI":"10.4049\/jimmunol.0802145","type":"journal-article","created":{"date-parts":[[2009,6,24]],"date-time":"2009-06-24T22:00:49Z","timestamp":1245880849000},"page":"1229-1237","source":"Crossref","is-referenced-by-count":21,"title":["Significance of N-Terminal Proteolysis of CCL14a to Activity on the Chemokine Receptors CCR1 and CCR5 and the Human Cytomegalovirus-Encoded Chemokine Receptor US28"],"prefix":"10.1093","volume":"183","author":[{"given":"Rudolf","family":"Richter","sequence":"first","affiliation":[{"name":"Institute of Transfusion Medicine and Immune Hematology, Blood Donation Service of the German Red Cross , Frankfurt,","place":["Germany"]},{"name":"Clinic of Immunology and Rheumatology, Hannover Medical School , Hannover,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Casarosa","sequence":"additional","affiliation":[{"name":"Leiden\/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Faculty of Chemistry , Amsterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludger","family":"St\u00e4ndker","sequence":"additional","affiliation":[{"name":"Clinic of Immunology and Rheumatology, Hannover Medical School , Hannover,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"M\u00fcnch","sequence":"additional","affiliation":[{"name":"Institute of Virology, University of Ulm , Ulm,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Yves","family":"Springael","sequence":"additional","affiliation":[{"name":"Institute of Interdisciplinary Research, Universit\u00e9 Libre de Bruxelles , Brussels,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia","family":"Nijmeijer","sequence":"additional","affiliation":[{"name":"Leiden\/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Faculty of Chemistry , Amsterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolf-Georg","family":"Forssmann","sequence":"additional","affiliation":[{"name":"Clinic of Immunology and Rheumatology, Hannover Medical School , Hannover,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry F","family":"Vischer","sequence":"additional","affiliation":[{"name":"Leiden\/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Faculty of Chemistry , Amsterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jalal","family":"Vakili","sequence":"additional","affiliation":[{"name":"Institute of Interdisciplinary Research, Universit\u00e9 Libre de Bruxelles , Brussels,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Detheux","sequence":"additional","affiliation":[{"name":"Euroscreen S.A. , Brussels,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Parmentier","sequence":"additional","affiliation":[{"name":"Institute of Interdisciplinary Research, Universit\u00e9 Libre de Bruxelles , Brussels,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rob","family":"Leurs","sequence":"additional","affiliation":[{"name":"Leiden\/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Faculty of Chemistry , Amsterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martine J","family":"Smit","sequence":"additional","affiliation":[{"name":"Leiden\/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Faculty of Chemistry , Amsterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,7,15]]},"reference":[{"key":"2026012811262832800_R1","first-page":"565","article-title":"Chemokines and leukocyte traffic.","volume-title":"Nature","year":"1998"},{"key":"2026012811262832800_R2","first-page":"121","article-title":"Chemokines: a new classification system and their role in immunity.","volume-title":"Immunity","year":"2000"},{"key":"2026012811262832800_R3","first-page":"123","article-title":"Lymphocyte traffic control by chemokines.","volume-title":"Nat. Immunol.","year":"2001"},{"key":"2026012811262832800_R4","first-page":"ii84","article-title":"Chemokines: role in inflammation and immune surveillance.","volume-title":"Ann. Rheum. Dis.","year":"2004"},{"key":"2026012811262832800_R5","first-page":"171","article-title":"Chemokines and their receptors: drug targets in immunity and inflammation.","volume-title":"Annu. Rev. Pharmacol. Toxicol.","year":"2008"},{"key":"2026012811262832800_R6","first-page":"661","article-title":"Identification of a major co-receptor for primary isolates of HIV-1.","volume-title":"Nature","year":"1996"},{"key":"2026012811262832800_R7","first-page":"667","article-title":"HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5.","volume-title":"Nature","year":"1996"},{"key":"2026012811262832800_R8","first-page":"833","article-title":"The CXC chemokine SDF-1 is the ligand for LESTR\/fusin and prevents infection by T-cell-line-adapted HIV-1.","volume-title":"Nature","year":"1996"},{"key":"2026012811262832800_R9","first-page":"6389","article-title":"The cytomegalovirus-encoded chemokine receptor US28 can enhance cell-cell fusion mediated by different viral proteins.","volume-title":"J. Virol.","year":"1998"},{"key":"2026012811262832800_R10","first-page":"855","article-title":"Chemokine sequestration by viral chemoreceptors as a novel viral escape strategy: withdrawal of chemokines from the environment of cytomegalovirus-infected cells.","volume-title":"J. Exp. Med.","year":"1998"},{"key":"2026012811262832800_R11","first-page":"56","article-title":"HCMV-encoded G-protein-coupled receptor as constitutively active modulators of cellular signaling networks.","volume-title":"Trends Pharmacol. Sci.","year":"2006"},{"key":"2026012811262832800_R12","first-page":"774","article-title":"Human cytomegalovirus encodes three G protein-coupled receptor homologues.","volume-title":"Nature","year":"1990"},{"key":"2026012811262832800_R13","first-page":"28539","article-title":"Human cytomegalovirus open reading frame US28 encodes a functional \u03b2 chemokine receptor.","volume-title":"J. Biol. Chem.","year":"1994"},{"key":"2026012811262832800_R14","first-page":"209","article-title":"Selective recognition of the membrane-bound CX3C chemokine, fractalkine, by the human cytomegalovirus-encoded broad-spectrum receptor US28.","volume-title":"FEBS Lett.","year":"1998"},{"key":"2026012811262832800_R15","first-page":"325","article-title":"The cytomegalovirus US28 protein binds multiple CC chemokines with high affinity.","volume-title":"Biochem. Biophys. Res. Commun.","year":"1995"},{"key":"2026012811262832800_R16","first-page":"295","article-title":"HCC-1, a novel chemokine from human plasma.","volume-title":"J. Exp. Med.","year":"1996"},{"key":"2026012811262832800_R17","first-page":"227","article-title":"Organization of the chemokine gene cluster on human chromosome 17q11.2 containing the genes for CC chemokine MPIF-1, HCC-2, HCC-1, LEC, and RANTES.","volume-title":"J. Interferon Cytokine Res.","year":"1999"},{"key":"2026012811262832800_R18","first-page":"6308","article-title":"HCC-2, a human chemokine: gene structure, expression pattern, and biological activity.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"1998"},{"key":"2026012811262832800_R19","first-page":"10799","article-title":"Posttranslationally processed forms of the human chemokine HCC-1.","volume-title":"Biochemistry","year":"2000"},{"key":"2026012811262832800_R20","first-page":"1501","article-title":"Natural proteolytic processing of hemofiltrate CC chemokine 1 generates a potent CC chemokine receptor (CCR)1 and CCR5 agonist with anti-HIV properties.","volume-title":"J. Exp. Med.","year":"2000"},{"key":"2026012811262832800_R21","first-page":"3406","article-title":"Urokinase plasminogen activator and plasmin efficiently convert hemofiltrate CC chemokine 1 into its active.","volume-title":"J. Immunol.","year":"2001"},{"key":"2026012811262832800_R22","first-page":"982","article-title":"Hemofiltrate CC chemokine 1(9\u201374) causes effective internalization of CCR5 and is a potent inhibitor of R5-tropic human immunodeficiency virus type 1 strains in primary T cells and macrophages.","volume-title":"Antimicrob. Agents Chemother.","year":"2002"},{"key":"2026012811262832800_R23","first-page":"125","article-title":"Peptide bank generated by large-scale preparation of circulating human peptides.","volume-title":"J. Chromatogr. A.","year":"1997"},{"key":"2026012811262832800_R24","first-page":"2299","article-title":"Laser desorption ionization of proteins with molecular masses exceeding 10,000 daltons.","volume-title":"Anal. Chem.","year":"1988"},{"key":"2026012811262832800_R25","first-page":"34719","article-title":"Multiple charged and aromatic residues in CCR5 amino-terminal domain are involved in high affinity binding of both chemokines and HIV-1 Env protein.","volume-title":"J. Biol. Chem.","year":"1999"},{"key":"2026012811262832800_R26","first-page":"4903","article-title":"CD26\/dipeptidyl-peptidase IV down-regulates the eosinophil chemotactic potency, but not the anti-HIV activity of human eotaxin by affecting its interaction with CC chemokine receptor 3.","volume-title":"J. Immunol.","year":"1999"},{"key":"2026012811262832800_R27","first-page":"1133","article-title":"Constitutive signaling of the human cytomegalovirus-encoded chemokine receptor US28.","volume-title":"J. Biol. Chem.","year":"2001"},{"key":"2026012811262832800_R28","first-page":"1328","article-title":"The rat cytomegalovirus R33-encoded G protein-coupled receptor signals in a constitutive fashion.","volume-title":"J. Virol.","year":"2002"},{"key":"2026012811262832800_R29","first-page":"8455","article-title":"Nef enhances human immunodeficiency virus type 1 infectivity and replication independently of viral coreceptor tropism.","volume-title":"J. Virol.","year":"2002"},{"key":"2026012811262832800_R30","first-page":"3456","article-title":"n-Nonanoyl-CC chemokine ligand 14, a potent CC chemokine ligand 14 analogue that prevents the recruitment of eosinophils in allergic airway inflammation.","volume-title":"J. Immunol.","year":"2004"},{"key":"2026012811262832800_R31","first-page":"2179","article-title":"Identification of aminopeptidase M as an enkephalin-inactivating enzyme in rat cerebral membranes.","volume-title":"Biochemistry","year":"1985"},{"key":"2026012811262832800_R32","first-page":"1299","article-title":"Human myeloid plasma membrane glycoprotein CD13 (gp150) is identical to aminopeptidase N.","volume-title":"J. Clin. Invest.","year":"1989"},{"key":"2026012811262832800_R33","first-page":"17","article-title":"Role of alanyl aminopeptidase in growth and function of human T cells (review).","volume-title":"Int. J. Mol. Med.","year":"1999"},{"key":"2026012811262832800_R34","first-page":"1874","article-title":"Identification of a chemokine receptor encoded by human cytomegalovirus as a cofactor for HIV-1 entry.","volume-title":"Science","year":"1997"},{"key":"2026012811262832800_R35","first-page":"1935","article-title":"Dipeptidyl peptidase IV (DP IV, CD26) and aminopeptidase N (APN, CD13) as regulators of T cell function and targets of immunotherapy in CNS inflammation.","volume-title":"Int. Immunopharmacol.","year":"2006"},{"key":"2026012811262832800_R36","first-page":"453","article-title":"CD13\/N-aminopeptidase is involved in the development of dendritic cells and macrophages from cord blood CD34+ cells.","volume-title":"Blood","year":"2000"},{"key":"2026012811262832800_R37","first-page":"1636","article-title":"CD13\/aminopeptidase N, a novel chemoattractant for T lymphocytes in pulmonary sarcoidosis.","volume-title":"Am. J. Respir. Crit. Care Med.","year":"2000"},{"key":"2026012811262832800_R38","first-page":"129","article-title":"Inactivation of interleukin-8 by aminopeptidase N (CD13).","volume-title":"J. Leukocyte Biol.","year":"1995"},{"key":"2026012811262832800_R39","first-page":"1262","article-title":"Natural truncation of RANTES abolishes signaling through the CC chemokine receptors CCR1 and CCR3, impairs its chemotactic potency and generates a CC chemokine inhibitor.","volume-title":"Eur. J. Immunol.","year":"1998"},{"key":"2026012811262832800_R40","first-page":"29839","article-title":"Kinetic investigation of chemokine truncation by CD26\/dipeptidyl peptidase IV reveals a striking selectivity within the chemokine family.","volume-title":"J. Biol. Chem.","year":"2001"},{"key":"2026012811262832800_R41","first-page":"1504","article-title":"Increase of expression and activation of chemokine CCL15 in chronic renal failure.","volume-title":"Biochem. Biophys. Res. Commun.","year":"2006"},{"key":"2026012811262832800_R42","first-page":"328","article-title":"The urokinase-type plasminogen activator\/ist soluble receptor system is independently related to carotid atherosclerosis and associated with CC-chemokines in uraemic patients.","volume-title":"Thromb. Res.","year":"2008"},{"key":"2026012811262832800_R43","first-page":"517","article-title":"Oxidative stress effects fibirnolytic system in dialysis uremic patients.","volume-title":"Thromb. Res.","year":"2006"},{"key":"2026012811262832800_R44","first-page":"283","article-title":"Lymphocyte 5\u2032-nucleotidase and aminopeptidase N activity in patients on maintenance hemodialysis treated with human recombinant erythropoietin and 1-\u03b1-D3.","volume-title":"Renal Fail.","year":"2005"},{"key":"2026012811262832800_R45","first-page":"215","article-title":"Serum levels of soluble CD26 and CD30 in patients on hemodialysis.","volume-title":"Nephron","year":"2002"},{"key":"2026012811262832800_R46","first-page":"226","article-title":"Identifying chemokines as therapeutic targets in renal disease: lessons from antagonist studies and knockout mice.","volume-title":"Kidney Blood Press. Res.","year":"2004"},{"key":"2026012811262832800_R47","first-page":"2075","article-title":"Role of the chemokine decoy receptor D6 in balancing inflammation, immune activation, and antimicrobial resistance in Mycobacterium tuberculosis infection.","volume-title":"J. Exp. Med.","year":"2008"},{"key":"2026012811262832800_R48","first-page":"197","article-title":"Regulation of chemokine activity by posttranslational modification.","volume-title":"Pharmacol. Ther.","year":"2008"},{"key":"2026012811262832800_R49","first-page":"9642","article-title":"Distinct but overlapping epitopes for the interaction of a CC-chemokine with CCR1, CCR3 and CCR5.","volume-title":"Biochemistry","year":"1997"},{"key":"2026012811262832800_R50","first-page":"13548","article-title":"Characterization of the role of the N-loop of MIP-1\u03b2 in CCR5 binding.","volume-title":"Biochemistry","year":"2002"},{"key":"2026012811262832800_R51","first-page":"3401","article-title":"CC chemokine MIP-1\u03b2 can function as a monomer and depends on Phe13 for receptor binding.","volume-title":"Biochemistry","year":"2000"},{"key":"2026012811262832800_R52","first-page":"10782","article-title":"Structural comparison of monomeric variants of the chemokine MIP-1\u03b2 having differing ability to bind the receptor CCR5.","volume-title":"Biochemistry","year":"2001"},{"key":"2026012811262832800_R53","first-page":"13013","article-title":"Identification of residues in the monocyte chemotactic protein-1 that contact MCP-1 receptor, CCR2.","volume-title":"Biochemistry","year":"1999"},{"key":"2026012811262832800_R54","first-page":"3275","article-title":"CC and CX3C chemokines differentially interact with the N terminus of the human cytomegalovirus-encoded US28 receptor.","volume-title":"J. Biol. Chem.","year":"2005"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/183\/2\/1229\/62697518\/9332.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/183\/2\/1229\/62697518\/9332.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T16:29:09Z","timestamp":1769617749000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/183\/2\/1229\/8053551"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,7]]},"references-count":54,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2009,7,15]]},"published-print":{"date-parts":[[2009,7,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.0802145","relation":{},"ISSN":["1550-6606","0022-1767"],"issn-type":[{"value":"1550-6606","type":"electronic"},{"value":"0022-1767","type":"print"}],"subject":[],"published-other":{"date-parts":[[2009,7]]},"published":{"date-parts":[[2009,7]]}}}