Granzyme B-dependent proteolysis acts as a switch to enhance the proinflammatory activity of IL-1α.
AuthorsAfonina, Inna S
Tynan, Graham A
Logue, Susan E
Cullen, Sean P
Lüthi, Alexander U
Reeves, Emer P
McElvaney, Noel G
Medema, Jan P
Lavelle, Ed C
Martin, Seamus J
AffiliationMolecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland.
Human Umbilical Vein Endothelial Cells
Mice, Inbred BALB C
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CitationGranzyme B-dependent proteolysis acts as a switch to enhance the proinflammatory activity of IL-1α. 2011, 44 (2):265-78 Mol. Cell
AbstractGranzyme 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.
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