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 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.
Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland.
Inna S
IS
Afonina
Graham A
GA
Tynan
Susan E
SE
Logue
Sean P
SP
Cullen
Michael
M
Bots
Alexander U
AU
Lüthi
Emer P
EP
Reeves
Noel G
NG
McElvaney
Jan P
JP
Medema
Ed C
EC
Lavelle
Seamus J
SJ
Martin
D000818:Animals; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D053804:Granzymes / Q000378:metabolism*; D006367:HeLa Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D053582:Interleukin-1alpha / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D059748:Proteolysis
D016207:Cytokines; D053582:Interleukin-1alpha; D053804:Granzymes