The human neutrophil lipocalin supports the allosteric activation of matrix metalloproteinases

The human neutrophil lipocalin (HNL), a member of the large family of lipoc alins that exhibit various physiological functions, is coexpressed in granu locytes with progelatinase B (MMP-9). Part of it is covalently bound to the proenzyme and therefore may play a possible role in the activation process : of promatrix metalloproteinases. We now report that HNL is able to accele rate the direct activation of promatrix metalloproteinases slightly. A sign ificant enhancement of the activity could be demonstrated for the HgCl2- an d the plasma kallikrein-induced activation of all three secretory forms of proMMP-9 and of proMMP-8. The same activating effects were exerted by HNL i solated from granulocytes as well as by the recombinant forms expressed by the yeast Pichia pastoris or by Escherichia coli. This demonstrates that th e carbohydrate moiety is not essential for the biological activity of HNL. Activation and activity enhancement are obviously mediated by entrapping th e remaining N-terminal sequence residues of the partially truncated proenzy me into the hydrophobic binding pocket of the HNL. In conclusion these resu lts document that HNL can exert an enzyme-activating effect in the regulati on of inflammatory and pathophysiological responses of granulocytes in the physiological activation of MMPs that have been subject to limited proteoly tic processing.