Gelatinase B/matrix metalloproteinase-9 and other neutrophil proteases switch off interleukin-2 activity.

Abstract

Interleukin 2 (IL-2) is critical for T cell development and homeostasis, being a key regulator of adaptive immune responses in autoimmunity, hypersensitivity reactions and cancer. Therefore, its abundance in serum and peripheral tissues needs tight control. Here, we described a new mechanism contributing to the immunobiology of IL-2. We demonstrated, both in biochemical and cell-based assays, that IL-2 is subject to proteolytic processing by neutrophil matrix metalloproteinase-9 (MMP-9). IL-2 fragments produced after cleavage by MMP-9 remained linked by a disulfide bond and displayed a reduced affinity for all IL-2 receptor subunits and a distinct pattern and timing of signal transduction. Stimulation of IL-2-dependent cells, including murine CTLL-2 and primary human regulatory T cells, with cleaved IL-2 resulted in significantly decreased proliferation. The concerted action of neutrophil proteases destroyed IL-2. Our data suggest that in neutrophil-rich inflammatory conditions in vivo, neutrophil MMP-9 may reduce the abundance of signaling-competent IL-2 and generate a fragment that competes with IL-2 for receptor binding, whereas the combined activity of granulocyte proteases has the potential to degrade and thus eliminate bioavailable IL-2.

• Authors: Vasily Rybakin, Melissa Stas, Estefania Ugarte-Berzal, Sam Noppen, Jennifer Vandooren, Ilse Van Aelst, Sandra Liekens, Paul Proost, Ghislain Opdenakker
• Journal: The Biochemical journal (Biochem J) Vol. 476 Issue 15 Pg. 2191-2208 (08 09 2019) ISSN: 1470-8728 [Electronic] England
• PMID: 31262730 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Chemical References

• IL2 protein, human
• Interleukin-2
• MMP9 protein, human
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse

Topics

• Animals
• Cell Line
• Humans
• Interleukin-2 (genetics, metabolism)
• Matrix Metalloproteinase 9 (genetics, metabolism)
• Mice
• Neutrophils (enzymology)
• Signal Transduction
• T-Lymphocytes, Regulatory (immunology)