Zusammenfassung
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 ...
Zusammenfassung
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.
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