Human proteinase 3 resistance to inhibition extends to alpha-2 macroglobulin

Polymorphonuclear neutrophils contain at least four serine endopeptidases, namely neutrophil elastase (NE), proteinase 3 (PR3), cathepsin G (CatG), and NSP4, which contribute to the regulation of infection and of inflammatory processes. In physiological conditions, endogenous inhibitors including alpha 2-macroglobulin (alpha 2-M), serpins [alpha 1-proteinase inhibitor (alpha 1-PI)], monocyte neutrophil elastase inhibitor (MNEI), alpha 1-antichymotrypsin, and locally produced chelonianins (elafin, SLPI) control excessive proteolytic activity of neutrophilic serine proteinases. In contrast to human NE (hNE), hPR3 is weakly inhibited by alpha 1-PI and MNEI but not by SLPI. alpha 2-M is a large spectrum inhibitor that traps a variety of proteinases in response to cleavage(s) in its bait region. We report here that alpha 2-M was more rapidly processed by hNE than hPR3 or hCatG. This was confirmed by the observation that the association between alpha 2-M and hPR3 is governed by a k(ass) in the