title: NH2- and COOH-terminal truncations of murine granulocyte chemotactic protein-2 augment the in vitro and in vivo neutrophil chemotactic potency.
abstract: Chemokines are important mediators of leukocyte migration during the inflammatory response. Post-translational modifications affect the biological potency of chemokines. In addition to previously identified NH2-terminally truncated forms, COOH-terminally truncated forms of the CXC chemokine murine granulocyte chemotactic protein-2 (GCP-2) were purified from conditioned medium of stimulated fibroblasts. The truncations generated 28 natural murine GCP-2 isoforms containing 69-92 residues, including most intermediate forms. Both NH2- and COOH-terminal truncations of GCP-2 resulted in enhanced chemotactic potency for human and murine neutrophils in vitro. The truncated isoform GCP-2(9-78) was 30-fold more potent than intact GCP-2(1-92)/LPS-induced CXC chemokine (LIX) at inducing an intracellular calcium increase in human neutrophils. After intradermal injection in mice, GCP-2(9-78) was also more effective than GCP-2(1-92)/LIX at inducing neutrophil infiltration. Similar to human IL-8 and GCP-2, murine GCP-2(9-78) and macrophage inflammatory protein-2 (MIP-2) induced calcium increases in both CXCR1 and CXCR2 transfectants. Murine GCP-2(9-78) could desensitize the calcium response induced by MIP-2 in human neutrophils and vice versa. Furthermore, MIP-2 and truncated GCP-2(9-78), but not intact GCP-2(1-92)/LIX, partially desensitized the calcium response to human IL-8 in human neutrophils. Taken together, these findings point to an important role of post-translationally modified GCP-2 to replace IL-8 in the mouse.
authors.affiliation: Laboratories ofMolecular Immunology and Immunobiology, Rega Institute for Medical Research, and Laboratory for Developmental Physiology and Molecular Biology, Zoological Institute, University of Leuven, Leuven, Belgium. anja.wuyts@rega.kuleuven.ac.be
authors.forename: A
authors.initials: A
authors.lastname: Wuyts
authors.forename: A
authors.initials: A
authors.lastname: D'Haese
authors.forename: V
authors.initials: V
authors.lastname: Cremers
authors.forename: P
authors.initials: P
authors.lastname: Menten
authors.forename: J P
authors.initials: JP
authors.lastname: Lenaerts
authors.forename: A
authors.initials: A
authors.lastname: De Loof
authors.forename: H
authors.initials: H
authors.lastname: Heremans
authors.forename: P
authors.initials: P
authors.lastname: Proost
authors.forename: J
authors.initials: J
authors.lastname: Van Damme
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D020013:Calcium Signaling; D054426:Chemokine CXCL2; D054427:Chemokine CXCL6; D019743:Chemokines, CXC / Q000302:isolation & purification / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D015846:Monokines / Q000494:pharmacology; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000187:drug effects*; D010446:Peptide Fragments; D020033:Protein Isoforms / Q000302:isolation & purification / Q000494:pharmacology; D019707:Receptors, Chemokine / Q000235:genetics; D018123:Receptors, Interleukin / Q000235:genetics; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D016415:Sequence Alignment; D017384:Sequence Deletion; D013045:Species Specificity
chemical_list: D015703:Antigens, CD; C515503:CXCL6 protein, human; D054426:Chemokine CXCL2; D054427:Chemokine CXCL6; D019743:Chemokines, CXC; D015846:Monokines; D010446:Peptide Fragments; D020033:Protein Isoforms; D019707:Receptors, Chemokine; D018123:Receptors, Interleukin; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B