Linked Life Data

20483925

Source:http://linkedlifedata.com/resource/pubmed/id/20483925

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2010-8-3
pubmed:abstractText
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 49BBXB52 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 EC50 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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
1938-3673
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
88
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
383-92
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
CCR1- and CCR5-mediated inactivation of leukocytes by a nonglycosaminoglycan (non-GAG)-binding variant of n-nonanoyl-CCL14 (NNY-CCL14).
pubmed:affiliation
Center of Pharmacology and Toxicology, Clinic of Immunology and Rheumatology, Hannover Medical School, Feodor-Lynen-Strasse 31, 30625 Hannover, Germany. sgupta3@bidmc.harvard.edu
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't