Selective Proteolytic Cleavage of IL-2 Receptor and IL-6 Receptor Ligand Binding Chains by Neutrophil-Derived Serine Proteases at Foci of Inflammation

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.

Shedding of Endogenous Interleukin-6 Receptor (IL-6R) Is Governed by A Disintegrin and Metalloproteinase (ADAM) Proteases while a Full-length IL-6R Isoform Localizes to Circulating Microvesicles

“…DPPI activates neutrophil elastase, cathepsin G as well as proteinase 3 by excising dipeptides from the N terminus (38). Notably, cathepsin G has previously been implicated in human IL-6R shedding in an inflammatory setting (39). Although all three serine proteases are highly abundant in myeloid cells and therefore represent ideal candidate sheddases mediating the release of sIL-6R into the bloodstream, we were not able to detect significant differences between DPPI knock-out mice and control animals in terms of circulating sIL-6R levels.…”

“…proteolytically cleaved by cathepsin G (39). All three proteases must be activated by N-terminal removal of two amino acids, which is accomplished by dipeptidylpeptidase I (DPPI, or alternatively cathepsin C) (38).…”

Reactive Oxygen Species Regulate Neutrophil Recruitment and Survival in Pneumococcal Pneumonia

“…In keeping with this, our preliminary data have shown evidence of increased levels of secretory leukoprotease inhibitor, an inhibitor of neutrophil-expressed serine proteases, in gp91 phox2/-mice (see Figure E5). Neutrophil elastase can modify the inflammatory response by enhancing IL-8 production and inducing shedding of surface expressed receptors (43,44).…”

Elevated expression of polymorphonuclear leukocyte elastase in breast cancer tissue is associated with tamoxifen failure in patients with advanced disease

“…In addition to its described role in tumour cell invasion and metastasis, the serine protease PMN-E may, similar as has been suggested for uPA for human ovarian carcinoma cells (Fischer et al, 1998) and breast cancer cells (Foekens et al, 1995), provoke cell proliferation via enzymatic activation of several growth factor (receptor) pathways. In this respect, the ability of elastase to cleave or activate several growth factors or receptors, such as EGF and EGF receptor (Di Camillo et al, 2002), IL-2 and IL-6 receptor (Bank et al, 1999), stromal cellderived factor-1 (Valenzuela-Fernandez et al, 2002), supports such a local elastase-directed growth interfering mechanism.…”