Granzymes (lymphocyte serine proteases): characterization with natural and synthetic substrates and inhibitors

Kam, Chih-Min; Hudig, Dorothy; Powers, James C.

doi:10.1016/s0167-4838(99)00282-4

Cited by 140 publications

(117 citation statements)

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“…However, some trypsin inhibitors also inhibit GzmA. GzmA is bound and irreversibly inhibited in the circulation by two trypsin inhibitors, α-2 macroglobulin and antithrombin III (113). Extracellular GzmA complexed to proteoglycans is resistant to these two protease inhibitors (114).…”

Section: Gzma Endogenous Inhibitorsmentioning

confidence: 99%

Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death

Chowdhury

Lieberman

2008

Annu. Rev. Immunol.

552

580

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The granzymes are cell death-inducing enzymes, stored in the cytotoxic granules of cytotoxic T lymphocytes and natural killer cells, that are released during granule exocytosis when a specific virus-infected or transformed target cell is marked for elimination. Recent work suggests that this homologous family of serine esterases can activate at least three distinct pathways of cell death. This redundancy likely evolved to provide protection against pathogens and tumors with diverse strategies for evading cell death. This review discusses what is known about granzyme-mediated pathways of cell death as well as recent studies that implicate granzymes in immune regulation and extracellular proteolytic functions in inflammation.

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Section: Gzma Endogenous Inhibitorsmentioning

confidence: 99%

Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death

Chowdhury

Lieberman

2008

Annu. Rev. Immunol.

552

580

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“…Regardless, these findings suggest that thrombin is more effective than rGrA for promotion of IL-8 release in A549 cells. We have found that BLT-hydrolyzing activity of our rGrA is comparable to that of native GrA (Kam et al 2000;Hirayasu et al 2005). Therefore, the lower efficiency of rGrA compared with thrombin in the context of IL-8 release may not be attributed to the catalytic capacity of the recombinant enzyme.…”

Section: Resultsmentioning

confidence: 73%

“…Therefore, it is tempting to speculate that rGrA-promoted IL-8 release from A549 cells occurs via a mechanism partially involving activation of pro-IL-1b. The primary function of extracellular GrA would be the degradation of extracellular matrix for tissue remodeling (Hirayasu et al 2008;Kam et al 2000;Yoshikawa et al 2008a). It is therefore likely that the release of inflammatory mediators caused by extracellular GrA, if any, is secondary to tissue remodeling.…”

Section: Analysis Of the Involvement Of Par-1 Activation In Rgra-prommentioning

confidence: 99%

“…Granzyme A (GrA) is a serine protease with trypsin-like specificity of cleavage that is expressed in cytotoxic T-lymphocytes and natural killer cells (Kam et al 2000). This protease is believed to function by entering virus-infected cells and growing tumors via pores formed by perforin, which is also expressed in cytotoxic cells, and participating in the apoptosis induction of abnormal cells (Chowdhury and Lieberman 2008;Kam et al 2000).…”

Section: Introductionmentioning

confidence: 99%

“…This protease is believed to function by entering virus-infected cells and growing tumors via pores formed by perforin, which is also expressed in cytotoxic cells, and participating in the apoptosis induction of abnormal cells (Chowdhury and Lieberman 2008;Kam et al 2000). It has been found that GrA is also found in body fluids such as blood (Spaeny-Dekking et al 1998;Tremblay et al 2000) and that in the lung, GrA mRNA is expressed not only in cytotoxic lymphocytes infiltrating this tissue but also in alveolar type II epithelial cells and alveolar macrophages (Vernooy et al 2007).…”

Section: Introductionmentioning

confidence: 99%

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Granzyme A and thrombin differentially promote the release of interleukin-8 from alveolar epithelial A549 cells

et al. 2010

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Some of extracellular serine proteases with trypsin-like specificity of cleavage have been known to increase the release of inflammatory mediators from various cell types. For instance, two well-known trypsin-like serine proteases circulating in blood, granzyme A (GrA) and thrombin, have been found to promote interleukin (IL)-8 release from an alveolar epithelial A549 cell line. However, the mechanisms by which the proteases promote IL-8 release from the cells are not fully understood. In the present study, using A549 cells we found that (1) thrombin promoted IL-8 release from the cells via a mechanism partially involving activation of protease-activated receptor-1, a G-protein coupled receptor, whereas a recombinant form of GrA (rGrA) did it via a mechanism that does not involve the receptor activation; that (2) unlike rGrA, thrombin did not cause detachment and microtubule disruption of the cells; and that (3) the release of IL-8 induced by rGrA was inhibited in the presence of taxol, a microtubulestabilizing reagent, whereas that induced by thrombin was not. These findings suggest that rGrA and thrombin promote the release of IL-8 from A549 cells through distinct mechanisms.

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Granzymes

2004

Encyclopedic Dictionary of Genetics, Genomics and Proteomics

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Granzymes (lymphocyte serine proteases): characterization with natural and synthetic substrates and inhibitors

Cited by 140 publications

References 116 publications

Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death

Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death

Granzyme A and thrombin differentially promote the release of interleukin-8 from alveolar epithelial A549 cells

Granzymes

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