Granzyme K activates protease-activated receptor-1.
Granzyme K (GrK) is a trypsin-like serine protease that is elevated in patients with sepsis and acute lung inflammation. While GrK was originally believed to function exclusively as a pro-apoptotic protease, recent studies now suggest that GrK may possess other non-cytotoxic functions. In the contex...
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2011-01-01
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doaj-72a544f4ab3d4a539ffcd0acaf0d39c42020-11-25T02:33:55ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-0166e2148410.1371/journal.pone.0021484Granzyme K activates protease-activated receptor-1.Dawn M CooperDmitri V PechkovskyTillie L HackettDarryl A KnightDavid J GranvilleGranzyme K (GrK) is a trypsin-like serine protease that is elevated in patients with sepsis and acute lung inflammation. While GrK was originally believed to function exclusively as a pro-apoptotic protease, recent studies now suggest that GrK may possess other non-cytotoxic functions. In the context of acute lung inflammation, we hypothesized that GrK induces pro-inflammatory cytokine release through the activation of protease-activated receptors. The direct effect of extracellular GrK on PAR activation, intracellular signaling and cytokine was assessed using cultured human lung fibroblasts. Extracellular GrK induced secretion of IL-6, IL-8 and MCP-1 in a dose- and time-dependent manner in lung fibroblasts. Heat-inactivated GrK did not induce cytokine release indicating that protease activity is required. Furthermore, GrK induced activation of both the ERK1/2 and p38 MAP kinase signaling pathways, and significantly increased fibroblast proliferation. Inhibition of ERK1/2 abrogated the GrK-mediated cytokine release. Through the use of PAR-1 and PAR-2 neutralizing antibodies, it was determined that PAR-1 is essential for GrK-induced IL-6, IL-8 and MCP-1 release. In summary, extracellular GrK is capable of activating PAR-1 and inducing fibroblast cytokine secretion and proliferation.http://europepmc.org/articles/PMC3128063?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Dawn M Cooper Dmitri V Pechkovsky Tillie L Hackett Darryl A Knight David J Granville |
spellingShingle |
Dawn M Cooper Dmitri V Pechkovsky Tillie L Hackett Darryl A Knight David J Granville Granzyme K activates protease-activated receptor-1. PLoS ONE |
author_facet |
Dawn M Cooper Dmitri V Pechkovsky Tillie L Hackett Darryl A Knight David J Granville |
author_sort |
Dawn M Cooper |
title |
Granzyme K activates protease-activated receptor-1. |
title_short |
Granzyme K activates protease-activated receptor-1. |
title_full |
Granzyme K activates protease-activated receptor-1. |
title_fullStr |
Granzyme K activates protease-activated receptor-1. |
title_full_unstemmed |
Granzyme K activates protease-activated receptor-1. |
title_sort |
granzyme k activates protease-activated receptor-1. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2011-01-01 |
description |
Granzyme K (GrK) is a trypsin-like serine protease that is elevated in patients with sepsis and acute lung inflammation. While GrK was originally believed to function exclusively as a pro-apoptotic protease, recent studies now suggest that GrK may possess other non-cytotoxic functions. In the context of acute lung inflammation, we hypothesized that GrK induces pro-inflammatory cytokine release through the activation of protease-activated receptors. The direct effect of extracellular GrK on PAR activation, intracellular signaling and cytokine was assessed using cultured human lung fibroblasts. Extracellular GrK induced secretion of IL-6, IL-8 and MCP-1 in a dose- and time-dependent manner in lung fibroblasts. Heat-inactivated GrK did not induce cytokine release indicating that protease activity is required. Furthermore, GrK induced activation of both the ERK1/2 and p38 MAP kinase signaling pathways, and significantly increased fibroblast proliferation. Inhibition of ERK1/2 abrogated the GrK-mediated cytokine release. Through the use of PAR-1 and PAR-2 neutralizing antibodies, it was determined that PAR-1 is essential for GrK-induced IL-6, IL-8 and MCP-1 release. In summary, extracellular GrK is capable of activating PAR-1 and inducing fibroblast cytokine secretion and proliferation. |
url |
http://europepmc.org/articles/PMC3128063?pdf=render |
work_keys_str_mv |
AT dawnmcooper granzymekactivatesproteaseactivatedreceptor1 AT dmitrivpechkovsky granzymekactivatesproteaseactivatedreceptor1 AT tillielhackett granzymekactivatesproteaseactivatedreceptor1 AT darrylaknight granzymekactivatesproteaseactivatedreceptor1 AT davidjgranville granzymekactivatesproteaseactivatedreceptor1 |
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