Granulocyte chemotactic protein 2 acts via both IL-8 receptors, CXCR1 and CXCR2

Eur J Immunol. 1998 Jan;28(1):164-70. doi: 10.1002/(SICI)1521-4141(199801)28:01<164::AID-IMMU164>3.0.CO;2-S.


Interleukin-8 (IL-8) acts on human neutrophils via two receptors, CXCR1 and CXCR2. It shares CXCR2 with all neutrophil-activating chemokines, which like IL-8 have a conserved Glu-Leu-Arg (ELR) N-terminal motif, but is generally considered to be the only relevant agonist for CXCR1. IL-8 has a basic residue at the sixth position after the second cysteine, which was suggested to contribute to CXCR1 specificity. Among the other ELR chemokines, only granulocyte chemotactic protein 2 (GCP-2) has such a basic determinant. Using Jurkat cells that stably express either CXCR1 or CXCR2, we studied receptor activation by IL-8, GCP-2 epithelial neutrophil-activating protein 2 (ENA-78) (which shares 77% identical amino acids with GCP-2) and growth-regulated oncogene alpha (GRO alpha). At 10 nM and higher concentrations, GCP-2 and IL-8 induced significant activation of CXCR1-expressing cells, but no activity was found with GRO alpha and ENA-78. As expected, however, all four chemokines had similar activities on CXCR2-expressing cells. A variant of GCP-2 in which the basic residue, Arg20, was replaced by a glycine was synthesized. This derivative was ineffective on CXCR1, but was as active as wild-type GCP-2 in CXCR2-expressing cells. GCP-2 displaced radiolabeled IL-8 from both receptors with low affinity, and in this respect resembled ENA-78 and GRO alpha. Our data show that GCP-2 acts via both IL-8 receptors and thus appears to be functionally more similar to IL-8 than to the other ELR chemokines. Activation of CXCR1 appears to depend significantly on the presence of a basic binding determinant close to the second cysteine.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Antigens, CD / drug effects*
  • Chemokine CXCL1
  • Chemokine CXCL5
  • Chemokine CXCL6
  • Chemokines / pharmacology*
  • Chemokines, CXC*
  • Chemotactic Factors / pharmacology
  • Chemotaxis, Leukocyte / drug effects
  • Growth Substances / pharmacology
  • Humans
  • Intercellular Signaling Peptides and Proteins*
  • Interleukin-8 / analogs & derivatives
  • Interleukin-8 / pharmacology
  • Jurkat Cells
  • Molecular Sequence Data
  • Pancreatic Elastase / metabolism
  • Protein Binding
  • Receptors, Chemokine / drug effects*
  • Receptors, Interleukin / drug effects*
  • Receptors, Interleukin-8A
  • Receptors, Interleukin-8B
  • Recombinant Fusion Proteins / drug effects
  • Structure-Activity Relationship
  • Transfection


  • Antigens, CD
  • CXCL1 protein, human
  • CXCL5 protein, human
  • CXCL6 protein, human
  • Chemokine CXCL1
  • Chemokine CXCL5
  • Chemokine CXCL6
  • Chemokines
  • Chemokines, CXC
  • Chemotactic Factors
  • Growth Substances
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-8
  • Receptors, Chemokine
  • Receptors, Interleukin
  • Receptors, Interleukin-8A
  • Receptors, Interleukin-8B
  • Recombinant Fusion Proteins
  • Pancreatic Elastase