Gupta, Shipra and Rieder, Sebastian and Richter, Rudolf and Schulz-Maronde, Sandra and Manns, Johanna and Escher, Sylvia E. and Heitland, Aleksandra and Mack, Matthias and Forssmann, Wolf-Georg and Elsner, Joern and Forssmann, Ulf (2010) CCR1- and CCR5-mediated inactivation of leukocytes by a nonglycosaminoglycan (non-GAG)-binding variant of n-Nonanoyl-CCL14 (NNY-CCL14). JOURNAL OF LEUKOCYTE BIOLOGY, 88 (2). pp. 383-392. ISSN 0741-5400,
Full text not available from this repository. (Request a copy)Abstract
Intervention on chemokine receptors to prevent directional leukocyte migration is a potential therapeutic strategy. NNY-CCL14 is a CD26-resistant lead molecule, which exerts its effects on multiple chemokine receptors (CCR1, CCR2, CCR3, and CCR5). The inhibitory effects of NNY-CCL14 in murine models of allergic airway inflammation have been assigned to its interaction with CCR1 and CCR5. In this study, a non-GAG-binding variant of NNY-CCL14 was generated by mutating basic amino acids within the identified GAG-binding (49)BBXB(52) motif. This CD26-resistant, non-GAG binding variant, NNY-CCL14(G, A), does not promote CCR1-dependent cell arrest on modeled endothelium. Its biological activity tested on human and murine chemokine receptors revealed distinguishing properties to NNY-CCL14. As suggested by EC(50) values for intracellular calcium mobilization, NNY-CCL14(G, A) demonstrated a reduced ability to activate hCCR1, but internalization and desensitization of hCCR1 were unperturbed. Surprisingly, its activity on hCCR3 was strongly reduced, and it did not internalize mCCR3. A significantly reduced chemotactic activity of eosinophils and monocytes was observed. All biological effects mediated by NNY-CCL14(G, A) via hCCR5 and mCCR5 showed no difference to NNY-CCL14. In mice treated i.v. with NNY-CCL14(G, A), a sustained in vivo down-modulation of CCR5 was achieved over 3 h. Therefore, NNY-CCL14(G, A) inactivates leukocytes by desensitizing and internalizing multiple chemokine receptors, thus rendering them unresponsive to further stimulation by natural ligands. When administered systemically, NNY-CCL14(G, A) may modulate leukocyte functions prior to their interaction with other endothelium-bound chemokines expressed under pathophysiological conditions, such as allergic inflammation. J. Leukoc. Biol. 88: 383-392; 2010.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ALLERGIC AIRWAY INFLAMMATION; GLYCOSAMINOGLYCAN-BINDING; CHEMOKINE RECEPTORS; HEPARAN-SULFATE; IN-VIVO; OLIGOMERIZATION; ASTHMA; RANTES; EOSINOPHILS; RECRUITMENT; allergy; chemokine; leukocytes; glycosaminoglycan |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Abteilung für Nephrologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 20 Jul 2020 10:32 |
| Last Modified: | 20 Jul 2020 10:32 |
| URI: | https://pred.uni-regensburg.de/id/eprint/24398 |
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