4.6 Article

Granzyme K Activates Protease-Activated Receptor-1

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PLOS ONE
卷 6, 期 6, 页码 -

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PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0021484

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资金

  1. British Columbia Lung Association [DJG:20R64011]
  2. Natural Sciences Engineering Research Council (NSERC)
  3. Canadian Institutes for Health Research (CIHR) IMPACT
  4. Heart & Stroke Foundation of Canada
  5. CIHR/Candian Lung Association/GSK
  6. IMPACT
  7. Michael Smith Foundation for Health Research (MSFHR)

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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.

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