Gelatinase B/MMP-9 and neutrophil collagenase/MMP-8 process the chemokines human GCP-2/CXCL6, ENA-78/CXCL5 and mouse GCP-2/LIX and modulate their physiological activities

Eur J Biochem. 2003 Sep;270(18):3739-49. doi: 10.1046/j.1432-1033.2003.03760.x.


On chemokine stimulation, leucocytes produce and secrete proteolytic enzymes for innate immune defence mechanisms. Some of these proteases modify the biological activity of the chemokines. For instance, neutrophils secrete gelatinase B (matrix metalloproteinase-9, MMP-9) and neutrophil collagenase (MMP-8) after stimulation with interleukin-8/CXCL8 (IL-8). Gelatinase B cleaves and potentiates IL-8, generating a positive feedback. Here, we extend these findings and compare the processing of the CXC chemokines human and mouse granulocyte chemotactic protein-2/CXCL6 (GCP-2) and the closely related human epithelial-cell derived neutrophil activating peptide-78/CXCL5 (ENA-78) with that of human IL-8. Human GCP-2 and ENA-78 are cleaved by gelatinase B at similar rates to IL-8. In addition, GCP-2 is cleaved by neutrophil collagenase, but at a lower rate. The cleavage of GCP-2 is exclusively N-terminal and does not result in any change in biological activity. In contrast, ENA-78 is cleaved by gelatinase B at eight positions at various rates, finally generating inactive fragments. Physiologically, sequential cleavage of ENA-78 may result in early potentiation and later in inactivation of the chemokine. Remarkably, in the mouse, which lacks IL-8 which is replaced by GCP-2/LIX as the most potent neutrophil activating chemokine, N-terminal clipping and twofold potentiation by gelatinase B was also observed. In addition to the similarities in the potentiation of IL-8 in humans and GCP-2 in mice, the conversion of mouse GCP-2/LIX by mouse gelatinase B is the fastest for any combination of chemokines and MMPs so far reported. This rapid conversion was also performed by crude neutrophil granule secretion under physiological conditions, extending the relevance of this proteolytic cleavage to the in vivo situation.

Publication types

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

MeSH terms

  • Animals
  • Calcium / chemistry
  • Calcium / metabolism
  • Cell Degranulation / drug effects
  • Cell Degranulation / physiology
  • Chemokine CXCL5
  • Chemokine CXCL6
  • Chemokines, CXC / chemistry
  • Chemokines, CXC / genetics
  • Chemokines, CXC / metabolism*
  • Chemokines, CXC / physiology
  • Enzyme Activation / drug effects
  • Humans
  • Interleukin-8 / analogs & derivatives*
  • Interleukin-8 / metabolism*
  • Interleukin-8 / physiology
  • Kinetics
  • Matrix Metalloproteinase 3 / pharmacology
  • Matrix Metalloproteinase 8 / blood
  • Matrix Metalloproteinase 8 / metabolism*
  • Matrix Metalloproteinase 9 / blood
  • Matrix Metalloproteinase 9 / metabolism*
  • Mice
  • Neutrophil Activation / physiology
  • Neutrophils / enzymology*
  • Phenylmercuric Acetate / analogs & derivatives
  • Phenylmercuric Acetate / pharmacology
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Spectrometry, Mass, Electrospray Ionization / methods


  • CXCL5 protein, human
  • CXCL6 protein, human
  • Chemokine CXCL5
  • Chemokine CXCL6
  • Chemokines, CXC
  • Cxcl5 protein, mouse
  • Interleukin-8
  • Recombinant Proteins
  • Matrix Metalloproteinase 3
  • Matrix Metalloproteinase 8
  • Matrix Metalloproteinase 9
  • Phenylmercuric Acetate
  • Calcium