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Research article - Peer-reviewed, 2019

Highly Selective Cleavage of TH2-Promoting Cytokines by the Human and the Mouse Mast Cell Tryptases, Indicating a Potent Negative Feedback Loop on TH2 Immunity

Fu, Zhirong; Akula, Srinivas; Thorpe, Michael; Hellman, Lars

Abstract

Mast cells (MC) are resident tissue cells found primarily at the interphase between tissues and the environment. These evolutionary old cells store large amounts of proteases within cytoplasmic granules, and one of the most abundant of these proteases is tryptase. To look deeper into the question of their in vivo targets, we have analyzed the activity of the human MC tryptase on 69 different human cytokines and chemokines, and the activity of the mouse tryptase (mMCP-6) on 56 mouse cytokines and chemokines. These enzymes were found to be remarkably restrictive in their cleavage of these potential targets. Only five were efficiently cleaved by the human tryptase: TSLP, IL-21, MCP3, MIP-3b, and eotaxin. This strict specificity indicates a regulatory function of these proteases and not primarily as unspecific degrading enzymes. We recently showed that the human MC chymase also had a relatively strict specificity, indicating that both of these proteases have regulatory functions. One of the most interesting regulatory functions may involve controlling excessive TH2-mediated inflammation by cleaving several of the most important TH2-promoting inflammatory cytokines, including IL-18, IL-33, TSLP, IL-15, and IL-21, indicating a potent negative feedback loop on TH2 immunity.

Keywords

mast cell; tryptase; chymase; serine protease; human chymase; cleavage specificity; cytokine; chemokine; TH2

Published in

International Journal of Molecular Sciences
2019, Volume: 20, number: 20, article number: 5147
Publisher: MDPI

    UKÄ Subject classification

    Biochemistry and Molecular Biology

    Publication identifier

    DOI: https://doi.org/10.3390/ijms20205147

    Permanent link to this page (URI)

    https://res.slu.se/id/publ/110826