Abstract
In two recent studies we have shown that three of the most abundant human hematopoietic serine proteases—mast cell chymase, mast cell tryptase and neutrophil cathepsin G—show a highly selective cleavage of cytokines and chemokines with a strong preference for a few alarmins, including IL-18, TSLP and IL-33. To determine if this is a general pattern for many of the hematopoietic serine proteases we have analyzed the human neutrophil elastase (hNE) and human proteinase 3 (hPR-3) for their cleavage of a panel of 69 different human cytokines and chemokines. Our results showed that these two latter enzymes, in sharp contrast to the two previous, had a very potent and relatively unrestrictive cleavage on this panel of targets. Almost all of these proteins were cleaved and many of them were fully degraded. In light of the proteases abundance and their colocalization, it is likely that together they have a very potent degrading activity on almost any protein in the area of neutrophil activation and granule release, including both foreign bacterial or viral proteins as well as various self-proteins in the area of inflammation/infection. However, a few very interesting exceptions to this pattern were found indicating a high resistance to degradation of some cytokines and chemokines, including TNF-α, IL-5, M-CSF, Rantes, IL-8 and MCP-1. All of these are either important for monocyte-macrophage, neutrophil or eosinophil proliferation, recruitment and activation, suggesting that cytokines/chemokines and proteases may have coevolved to not block the recruitment of monocytes–macrophages, neutrophils and possibly eosinophils during an inflammatory response involving neutrophil activation.
Highlights
Large amounts of immune mediators are found within cytoplasmic granules in cells of several of the major hematopoietic cell lineages
In two recent studies of the human mast cell chymase (HC), the human tryptase and hCG, we have shown that these three enzymes are very selective in their cleavage of a large panel of cytokines and chemokines
The HC only cleaved four cytokines and chemokines out of a panel of 51, which shows a high selectivity for this mast cell specific protease [10]
Summary
Large amounts of immune mediators are found within cytoplasmic granules in cells of several of the major hematopoietic cell lineages. This emphysema is thought to primarily be caused by excessive cleavage of extracellular and cell surface proteins of the lung epithelium by hNE, which results in plasma leakage [12,13,14] This phenomenon has indicated that these enzymes are very potent, which together with and a relatively low specificity results in major effects on the tissue or parasite target when released from the neutrophil in the area of infection or inflammation. In order to study the effect on cytokine cleavage by a combination of these enzymes we tested a panel of the cytokines by simultaneous cleavage using three of these enzymes: hNE, hPR-3 and hCG These three are the most abundant and the most active of the four neutrophil proteases and by assaying them together will thereby most likely give a good view of the total proteolytic activity of an activated neutrophil. TNF-α, FGF-2, BMP-14, EGF, MCP-1 RANTES and IL-1RA were relatively resistant to cleavage by the combination of three enzymes
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