2011
DOI: 10.1016/j.molcel.2011.07.037
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Granzyme B-Dependent Proteolysis Acts as a Switch to Enhance the Proinflammatory Activity of IL-1α

Abstract: 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 vit… Show more

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Cited by 246 publications
(235 citation statements)
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“…S2). Moreover, other proteases, including granzymes, matrix metalloprotease 9, and mast cell chymase, have been shown to process IL-1α, IL-1β, and IL-18 precursors into active cytokines (1,3,36,44). It remains to be seen whether these or other proteases may also play a role in the processing of IL-33 into mature bioactive forms.…”
Section: Discussionmentioning
confidence: 99%
“…S2). Moreover, other proteases, including granzymes, matrix metalloprotease 9, and mast cell chymase, have been shown to process IL-1α, IL-1β, and IL-18 precursors into active cytokines (1,3,36,44). It remains to be seen whether these or other proteases may also play a role in the processing of IL-33 into mature bioactive forms.…”
Section: Discussionmentioning
confidence: 99%
“…27,28,[31][32][33] GzmB can also regulate inflammation by cleaving and activating cytokines such as IL-18 and IL-1a. 34,35 Interestingly, it is also known that GzmB-mediated cleavage of IL-1a can occur extracellularly by GzmB derived from NK cells, 35 further highlighting the potential importance of perforin-independent GzmB activity in health and disease. In fact, both cytotoxic and non-cytotoxic activities of GzmB are suggested to have a role in many inflammatory disorders such as diabetes, cancer, transplant rejection, autoimmunity, cardiovascular and pulmonary diseases (reviewed in refs [36][37][38][39][40] ).…”
Section: Discussionmentioning
confidence: 99%
“…These findings imply that IL-1␣ precursor processing may be required for full function and suggest that the regulated expression and subsequent processing of IL-1␣ are of functional significance. Recent evidence in immune cells supports this possibility, demonstrating that the processed form of IL-1␣ is more effective in inducing the production of inflammatory mediators (10).…”
mentioning
confidence: 98%