The Positively Charged COOH-terminal Glycosaminoglycan-binding CXCL9(74-103) Peptide Inhibits CXCL8-induced Neutrophil Extravasation and Monosodium Urate Crystal-induced Gout in Mice
| Autor: | Nele Berghmans, Mauro M. Teixeira, Jo Van Damme, Rik Janssens, Paul Proost, Isabelle Ronsse, Daiane Boff, Andreas J. Kungl, Flávio A. Amaral, Anneleen Mortier, Vincent Vanheule, Nikola Kitic |
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| Přispěvatelé: | Clinical Biology |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
musculoskeletal diseases
Chemokine mice Gout Neutrophils Cell Migration Inhibition/drug effects Immunology Molecular Sequence Data Anti-Inflammatory Agents Peptide CXCR3 Peptides/chemistry Chemokine CXCL9 Biochemistry stomatognathic system uric acid immune system diseases Animals Humans Interleukin 8 Amino Acid Sequence Gout/chemically induced skin and connective tissue diseases Molecular Biology Glycosaminoglycans chemistry.chemical_classification Glycosaminoglycan binding Neutrophil extravasation biology Interleukin-8 Interleukin-8/antagonists & inhibitors Neutrophils/cytology Chemotaxis Cell Biology Chemokine CXCL9/chemistry Cell biology Mice Inbred C57BL Chemotaxis Leukocyte stomatognathic diseases chemistry Cell Migration Inhibition biology.protein Anti-Inflammatory Agents/chemistry CXCL9 Glycosaminoglycans/immunology Peptides Chemotaxis Leukocyte/drug effects |
| Popis: | The ELR(-)CXC chemokine CXCL9 is characterized by a long, highly positively charged COOH-terminal region, absent in most other chemokines. Several natural leukocyte- and fibroblast-derived COOH-terminally truncated CXCL9 forms missing up to 30 amino acids were identified. To investigate the role of the COOH-terminal region of CXCL9, several COOH-terminal peptides were chemically synthesized. These peptides display high affinity for glycosaminoglycans (GAGs) and compete with functional intact chemokines for GAG binding, the longest peptide (CXCL9(74-103)) being the most potent. The COOH-terminal peptide CXCL9(74-103) does not signal through or act as an antagonist for CXCR3, the G protein-coupled CXCL9 receptor, and does not influence neutrophil chemotactic activity of CXCL8 in vitro. Based on the GAG binding data, an anti-inflammatory role for CXCL9(74-103) was further evidenced in vivo. Simultaneous intravenous injection of CXCL9(74-103) with CXCL8 injection in the joint diminished CXCL8-induced neutrophil extravasation. Analogously, monosodium urate crystal-induced neutrophil migration to the tibiofemural articulation, a murine model of gout, is highly reduced by intravenous injection of CXCL9(74-103). These data show that chemokine-derived peptides with high affinity for GAGs may be used as anti-inflammatory peptides; by competing with active chemokines for binding and immobilization on GAGs, these peptides may lower chemokine presentation on the endothelium and disrupt the generation of a chemokine gradient, thereby preventing a chemokine from properly performing its chemotactic function. The CXCL9 peptide may serve as a lead molecule for further development of inhibitors of inflammation based on interference with chemokine-GAG interactions. ispartof: Journal of Biological Chemistry vol:290 issue:35 pages:21292-304 ispartof: location:United States status: published |
| Databáze: | OpenAIRE |
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