Calprotectin inhibits matrix metalloproteinases by sequestration of zinc

B Isaksen and M K Fagerhol

Department of Immunology and Transfusion Medicine, Ullevaal University Hospital, Kirkeveien 166, 0407 Oslo, Norway

Correspondence to:
Dr Isaksen barbro.isaksen{at}ulleval.no

Background/Aims—Calprotectin, a 36 kDa protein present in neutrophil cytoplasm, has antimicrobial and apoptosis inducing activities, which are reversed by the addition of zinc. Matrix metalloproteinases (MMPs), a family of zinc dependent enzymes, are important in many normal biological processes including embryonic development, angiogenesis, and wound healing, but also pathological processes such as inflammation, cancer, and tissue destruction. The aim of this study was to investigate whether calprotectin can inhibit MMP activity, and whether such inhibition could be overcome by the addition of zinc.

Methods—MMP activity was measured by the degradation of substrates precoated on to microwells, and visualised by Coomassie blue staining of residual substrate. Seven metalloproteinases (MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, and MMP-13) were tested against two substrates: gelatin and -casein.

Results—All MMPs except MMP-1 were active against gelatin, whereas MMP-7 was the only enzyme active against -casein. The addition of calprotectin inhibited the activity of all the MMPs, but different concentrations of the protein, from 0.3µM to > 11µM, were necessary to produce a 50% inhibition of the MMPs. Inhibition by calprotectin was largely overcome by the addition of zinc.

Conclusions—The findings suggest that calprotectin inhibits MMPs by sequestration of zinc. The data also suggest that MMPs have different affinities for zinc and that calprotectin has a lower zinc affinity than the MMPs.

Key Words: calprotectin • metalloproteinases • zinc

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