Granzyme B-Dependent Proteolysis Acts as a Switch to Enhance the Proinflammatory Activity of IL-1α

Granzyme B is a cytotoxic lymphocyte-derived protease that plays a central role in promoting apoptosis of virus-infected target cells, through direct proteolysis and activation of constituents of the cell death machinery. However, previous studies have also implicated granzymes A and B in the produc...

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Bibliographic Details
Published in:Molecular cell 2011-10, Vol.44 (2), p.265-278
Main Authors: Afonina, Inna S., Tynan, Graham A., Logue, Susan E., Cullen, Sean P., Bots, Michael, Lüthi, Alexander U., Reeves, Emer P., McElvaney, Noel G., Medema, Jan P., Lavelle, Ed C., Martin, Seamus J.
Format: Article
Language:English
Subjects:
Animals
apoptosis
calpain
cytokines
Cytokines - immunology
Cytokines - metabolism
cytotoxicity
elastase
Granzymes - metabolism
HeLa Cells
Human Umbilical Vein Endothelial Cells
Humans
Inflammation - immunology
Inflammation - metabolism
interleukin-1alpha
Interleukin-1alpha - metabolism
Mice
Mice, Inbred BALB C
proteases
Proteolysis
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Summary:Granzyme B is a cytotoxic lymphocyte-derived protease that plays a central role in promoting apoptosis of virus-infected target cells, through direct proteolysis and activation of constituents of the cell death machinery. However, previous studies have also implicated granzymes A and B in the production of proinflammatory cytokines, via a mechanism that remains undefined. Here we show that IL-1α is a substrate for granzyme B and that proteolysis potently enhanced the biological activity of this cytokine in vitro as well as in vivo. Consistent with this, compared with full-length IL-1α, granzyme B-processed IL-1α exhibited more potent activity as an immunoadjuvant in vivo. Furthermore, proteolysis of IL-1α within the same region, by proteases such as calpain and elastase, was also found to enhance its biological potency. Thus, IL-1α processing by multiple immune-related proteases, including granzyme B, acts as a switch to enhance the proinflammatory properties of this cytokine. [Display omitted] ► IL-1α is a substrate for the CTL/NK protease granzyme B ► Proteolysis of IL-1α by granzyme B potently enhanced the activity of this cytokine ► Proteolysis of IL-1α by calpain and elastase also enhanced bioactivity ► The IL-1α propeptide functions as a sensor for multiple proinflammatory proteases
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2011.07.037