NH2- and COOH-terminal truncations of murine granulocyte chemotactic protein-2 augment the in vitro and in vivo neutrophil chemotactic potency

J Immunol. 1999 Dec 1;163(11):6155-63.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antigens, CD / genetics
  • Calcium Signaling
  • Chemokine CXCL2
  • Chemokine CXCL6
  • Chemokines, CXC / isolation & purification
  • Chemokines, CXC / pharmacology*
  • Chemotaxis, Leukocyte*
  • Humans
  • Mice
  • Molecular Sequence Data
  • Monokines / pharmacology
  • Neutrophil Infiltration
  • Neutrophils / drug effects*
  • Peptide Fragments
  • Protein Isoforms / isolation & purification
  • Protein Isoforms / pharmacology
  • Receptors, Chemokine / genetics
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin-8A
  • Receptors, Interleukin-8B
  • Sequence Alignment
  • Sequence Deletion
  • Species Specificity

Substances

  • Antigens, CD
  • CXCL6 protein, human
  • Chemokine CXCL2
  • Chemokine CXCL6
  • Chemokines, CXC
  • Monokines
  • Peptide Fragments
  • Protein Isoforms
  • Receptors, Chemokine
  • Receptors, Interleukin
  • Receptors, Interleukin-8A
  • Receptors, Interleukin-8B