Abstract

Traumatic brain injuries induce a strong, locally restricted inflammatory response. Here we demonstrate that activated neutrophils infiltrate the site of tissue destruction and release large amounts of enzymatically active elastase, cathepsin G, and proteinase 3. High intracerebral protease concentrations were found to be accompanied by a reduced inhibitory potential at foci of inflammation. In 39 neurotrauma patients, a temporal correlation between the protease release from neutrophils and the solubilization of interleukin-2 (IL-2) receptor and IL-6 receptor ectodomains at sites of tissue destruction was observed, suggesting that neutrophil-derived proteases may play a crucial role in the cytokine receptor shedding at foci of inflammation. Under in vitro conditions, the cleavage of membrane-bound IL-2Ralpha was found to be predominantly catalyzed by elastase and, to a lesser extent, by proteinase 3. Cathepsin G was found to be incapable of solubilizing this receptor. In contrast, the cleavage of the IL-6R 80 kDa chain was catalyzed by cathepsin G but not by elastase or proteinase 3. The receptor fragments released by the action of these enzymes were found to retain their ligand-binding capacity. These results strongly suggest a pathophysiologic role of neutrophil-derived serine proteases, particularly in regulation of the expression of functional IL-2 and IL-6 receptors at foci of inflammation.