HUMAN NEUTROPHIL ELASTASE ABOLISHES INTERLEUKIN-8 CHEMOTACTIC ACTIVITY

A large body of literature supports the role of interlenkin-8 (IL-8) i n inflammatory lung disease, Numerous factors induce the local synthes is and secretion of this potent chemokine leading to the recruitment a nd activation of polymorphonuclear leukocytes, However, little is curr ently known about the fate of IL-8 secreted at sites of inflammatory i njury. We have found that incubation of recombinant human IL-8 with pu rified human neutrophil elastase (HNE) results in the lose of IL-8 che motactic activity in a dose- and time-dependent fashion, This loss in bioactivity is accompanied by a similar loss of IL-8 immunoreactivity, Western blot analysis revealed that IL-8 chemotactic activity is lost by proteolysis of the parent molecule into undetectable small fragmen ts, The terminal digestion of IL-8 was specific to HNE as no loss of b ioactivity was observed with equimolar concentrations of the serine pr oteases urokinase, plasmin, thrombin, or cathepsin G, This effect on c hemotactic activity is not limited to recombinant IL-8 because HNE als o digested IL-8 secreted by human monocytes. HNE-mediated proteolysis offers a novel mechanism for down-regulating the inflammatory cascade initiated by IL-8.