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A Colorimetric Assay that Specifically Measures Granzyme B Proteolytic Activity: Hydrolysis of Boc-Ala-Ala-Asp-S-Bzl
Published on: November 28, 2014
Human and mouse granzyme A induce a proinflammatory cytokine response
Sunil S Metkar1, Cheikh Menaa, Julian Pardo
1Department of Medicine, NorthShore University HealthSystem Research Institute, Evanston, IL 60201, USA.
Abstract:
Granzyme A (GzmA) is considered a major proapoptotic protease. We have discovered that GzmA-induced cell death involves rapid membrane damage that depends on the synergy between micromolar concentrations of GzmA and sublytic perforin (PFN). Ironically, GzmA and GzmB, independent of their catalytic activity, both mediated this swift necrosis. Even without PFN, lower concentrations of human GzmA stimulated monocytic cells to secrete proinflammatory cytokines (interleukin-1beta [IL-1beta], TNFalpha, and IL-6) that were blocked by a caspase-1 inhibitor. Moreover, murine GzmA and GzmA(+) cytotoxic T lymphocytes (CTLs) induce IL-1beta from primary mouse macrophages, and GzmA(-/-) mice resist lipopolysaccharide-induced toxicity. Thus, the granule secretory pathway plays an unexpected role in inflammation, with GzmA acting as an endogenous modulator.
Insights
Granzyme A (GzmA) causes rapid cell death via membrane damage, even without its catalytic activity. GzmA also triggers inflammatory cytokine release, highlighting its unexpected role in inflammation.
Area of Science:
- Immunology
- Cell Biology
Background:
- Granzyme A (GzmA) is primarily known as a proapoptotic protease.
- Its role in cell death and inflammation is not fully understood.
Purpose of the Study:
- To investigate the mechanisms of GzmA-induced cell death.
- To explore the non-catalytic functions of Granzymes in inflammation.
Main Methods:
- Studied GzmA-induced cell death in synergy with perforin (PFN).
- Assessed GzmA's effect on cytokine secretion in monocytic cells.
- Utilized GzmA knockout mice and GzmA-expressing cytotoxic T lymphocytes (CTLs).
Main Results:
- GzmA induces rapid necrotic cell death through membrane damage, requiring synergy with sublytic PFN.
- Both GzmA and Granzyme B (GzmB) mediate necrosis independently of catalytic activity.
- GzmA stimulates monocytic cells to secrete IL-1beta, TNFalpha, and IL-6, blocked by caspase-1 inhibition.
- Murine GzmA and CTLs induce IL-1beta in macrophages; GzmA knockout mice show resistance to LPS toxicity.
Conclusions:
- Granzyme A has a dual role in inducing rapid cell death and promoting inflammation.
- The granule secretory pathway is unexpectedly involved in inflammatory processes.
- GzmA acts as an endogenous modulator of inflammation, independent of its protease function.
