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Highly Selective Cleavage of Cytokines and Chemokines by the Human Mast Cell Chymase and Neutrophil Cathepsin G

Zhirong Fu, Michael Thorpe, Rahel Alemayehu, Ananya Roy, Jukka Kervinen, Lawrence de Garavilla, Magnus Åbrink and Lars Hellman
J Immunol January 4, 2017, 1601223; DOI: https://doi.org/10.4049/jimmunol.1601223
Zhirong Fu
*Department of Cell and Molecular Biology, Uppsala University, The Biomedical Center, SE-751 24 Uppsala, Sweden;
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Michael Thorpe
*Department of Cell and Molecular Biology, Uppsala University, The Biomedical Center, SE-751 24 Uppsala, Sweden;
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Rahel Alemayehu
†Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, SE-75007 Uppsala, Sweden;
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Ananya Roy
†Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, SE-75007 Uppsala, Sweden;
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Jukka Kervinen
‡Fraunhofer USA Center for Molecular Biotechnology, Newark, DE 19711; and
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Lawrence de Garavilla
§GDL Pharmaceutical Consulting and Contracting, Downingtown, PA 19335
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Magnus Åbrink
†Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, SE-75007 Uppsala, Sweden;
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Lars Hellman
*Department of Cell and Molecular Biology, Uppsala University, The Biomedical Center, SE-751 24 Uppsala, Sweden;
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Abstract

Human mast cell chymase (HC) and human neutrophil cathepsin G (hCG) show relatively similar cleavage specificities: they both have chymotryptic activity but can also cleave efficiently after leucine. Their relatively broad specificity suggests that they may cleave almost any substrate if present in high enough concentrations or for a sufficiently long time. A number of potential substrates have been identified for these enzymes and, recently, these enzymes have also been implicated in regulating cytokine activity by cleaving numerous cytokines and chemokines. To obtain a better understanding of their selectivity for various potential in vivo substrates, we analyzed the cleavage of a panel of 51 active recombinant cytokines and chemokines. Surprisingly, our results showed a high selectivity of HC; only 4 of 51 of these proteins were substantially cleaved. hCG cleaved a few additional proteins, although this occurred after adding almost equimolar amounts of enzyme to target. The explanation for this wide difference in activity against peptides or other linear substrates compared with native proteins is most likely related to the reduced accessibility of the enzymes to potential cleavage sites in folded proteins. In this article, we present evidence that sites not exposed on the surface of the protein are not cleaved by the enzyme. Interestingly, both enzymes readily cleaved IL-18 and IL-33, two IL-1–related alarmins, as well as the cytokine IL-15, which is important for T cell and NK cell homeostasis. Cleavage of the alarmins by HC and hCG suggests a function in regulating excessive inflammation.

Footnotes

  • This work was supported by Swedish National Research Council Grants 621-2011-5007 (to L.H.) and 521-2011-3533 (to M.Å.).

  • The online version of this article contains supplemental material.

  • Received July 13, 2016.
  • Accepted December 5, 2016.
  • Copyright © 2017 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 208 (11)
The Journal of Immunology
Vol. 208, Issue 11
1 Jun 2022
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Highly Selective Cleavage of Cytokines and Chemokines by the Human Mast Cell Chymase and Neutrophil Cathepsin G
Zhirong Fu, Michael Thorpe, Rahel Alemayehu, Ananya Roy, Jukka Kervinen, Lawrence de Garavilla, Magnus Åbrink, Lars Hellman
The Journal of Immunology January 4, 2017, 1601223; DOI: 10.4049/jimmunol.1601223

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Highly Selective Cleavage of Cytokines and Chemokines by the Human Mast Cell Chymase and Neutrophil Cathepsin G
Zhirong Fu, Michael Thorpe, Rahel Alemayehu, Ananya Roy, Jukka Kervinen, Lawrence de Garavilla, Magnus Åbrink, Lars Hellman
The Journal of Immunology January 4, 2017, 1601223; DOI: 10.4049/jimmunol.1601223
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