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,2
*Institute of Transfusion Medicine and Immune Hematology, Blood Donation Service of the German Red Cross, Frankfurt, Germany;
Clinic of Immunology and Rheumatology, Hannover Medical School, Hannover, Germany;
Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Faculty of Chemistry, Amsterdam, The Netherlands;
Institute of Virology, University of Ulm, Ulm, Germany;
¶Institute of Interdisciplinary Research, Université Libre de Bruxelles, Brussels, Belgium; and
||Euroscreen S.A., Brussels, Belgium
The CC chemokine CCL14a is constitutively expressed in a large variety of tissues and its inactive proform CCL14a(1–74) circulates in high concentrations in plasma. CCL14a(1–74) is converted into CCL14a(9–74) 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(12–74), 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(6–74)<(7–74)<(8–74)<<(9–74) = (10–74)>>(11–74)>>(12–74). The almost identical affinities of CCL14a(7–74), CCL14a(9–74), and CCL14a(10–74) 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(12–74) 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(9–74) to CCL14a(12–74) may involve the dipeptidase CD26/dipeptidyl peptidase IV (DPPIV), which generates CCL14a(11–74), and the metalloprotease aminopeptidase N (CD13), which displays the capacity to generate CCL14a(12–74) from CCL14a(11–74). Our results suggest that the activity of CCL14a might be regulated by stringent proteolytic activation and inactivation steps.
2 Address correspondence and reprint requests to Dr. Rudolf Richter, Institute of Transfusion Medicine and Immune Hematology, Blood Donation Service of the German Red Cross, 60528 Frankfurt, Germany. E-mail address: Rudorichter{at}gmx.de
1 This study was supported in part by a grant from the German Federal Ministry of Education and Research (Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie, Grant FKZ 0311815) and the Dutch Organization for Scientific Research (to H.F.V. and M.J.S.). This work was also supported by the Actions de Recherche Concertées of the Communauté Française de Belgique, the Interuniversity Attraction Poles Programme-Belgian State-Belgian Science Policy, the European Union (LSHB-CT-2005-518167/INNOCHEM), the Fonds de la Recherche Scientifique Médicale of Belgium, the Walloon Region (Programme d'Excellence "CIBLES"), the Fédération Belge contre le Cancer, and the Fondation Médicale Reine Elisabeth (to M.P.).
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