Cleavage of chemokines CCL2 and CXCL10 by matrix metalloproteinases-2 and -9: implications for chemotaxis.
Proteolytic processing of chemokines is a complex process that can result in dramatic effects on their chemotactic activity. Results from gel electrophoresis and mass spectrometry using recombinant CCL2 and CXCL10, incubated with either MMP-2 or -9, indicate that both chemokines are cleaved by the enzymes. N-terminal truncation of four amino acids from CCL2, and four or five residues from CXCL10 occurred, but removal of four residues from the C-terminus of CXCL10 was also observed with both MMPs. The speed of the reaction was chemokine-dependent, with N-terminal processing of CCL2 being complete within 3h, whereas activity of the MMPs on CXCL10 remained incomplete at 48h. The effect on the chemotactic potential of N-terminal truncation of CCL2 by MMPs-2 and -9 was investigated using in vitro migration assays. Monocytic cells exhibited a 2-fold reduction in migration to MMP-cleaved CCL2 variants, compared to intact CCL2.
Denney
Helen
H
Biomedical Research Centre, Faculty of Health and Wellbeing, Sheffield Hallam University, Sheffield, UK. h.a.denney@shu.ac.uk
Clench
Malcolm R
MR
Woodroofe
M Nicola
MN
D000595:Amino Acid Sequence; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism*; D002633:Chemotaxis; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary
C111835:CCL2 protein, human; C114753:CXCL10 protein, human; D018932:Chemokine CCL2; D054357:Chemokine CXCL10; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9