Binding of Activated Protein C to a Specific Receptor on Human Mononuclear Phagocytes Inhibits Intracellular Calcium Signaling and Monocyte-Dependent Proliferative Responses1,2

Hancock, Wayne W.; Grey, Shane T.; Hau, Lena; Akalin, Enver; Orthner, Carolyn L.; Sayegh, Mohamed H.; Salem, Hamed

doi:10.1097/00007890-199560120-00026

Cited by 122 publications

(81 citation statements)

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“…Expression profiling of EPCR + DCs and the entire CD11c hi DC population indeed revealed a remarkably complex effect of aPC treatment that was neither limited to EPCR + DCs nor strictly dependent on normal expression levels of PAR1 and EPCR and exhibited a markedly biphasic pattern. Such findings are entirely consistent with the notion that aPC not only engages the EPCR/PAR1 axis but interacts in addition with other signalingcompetent receptors, including apoE receptor-2 (apoER2/lrp8), glycoprotein 1bα (GP1bα) (54,55), CD11b/Mac-1 (F.J. Castellino, unpublished observation), and possibly as-yet-unknown aPC-selective receptors on monocytes (56). Integration of the dataset provided in Supplemental Excel file 1 with data from corresponding expression studies on mice lacking the various candidate receptors for aPC in specific cell types should eventually enable a systematic dissection of the specific intra- and intercellular pathways regulated by aPC over the time course of endotoxemia and infection.…”

Section: Discussionsupporting

confidence: 86%

Activated protein C targets CD8+ dendritic cells to reduce the mortality of endotoxemia in mice

Kerschen

Hernández²,

Zogg³

et al. 2010

J. Clin. Invest.

104

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Activated protein C (aPC) therapy reduces mortality in adult patients with severe sepsis. In mouse endotoxemia and sepsis models, mortality reduction requires the cell signaling function of aPC, mediated through protease-activated receptor-1 (PAR1) and endothelial protein C receptor (EPCR; also known as Procr). Candidate cellular targets of aPC include vascular endothelial cells and leukocytes. Here, we show that expression of EPCR and PAR1 on hematopoietic cells is required in mice for an aPC variant that mediates full cell signaling activity but only minimal anticoagulant function (5A-aPC) to reduce the mortality of endotoxemia. Expression of EPCR in mature murine immune cells was limited to a subset

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Section: Discussionsupporting

confidence: 86%

Activated protein C targets CD8+ dendritic cells to reduce the mortality of endotoxemia in mice

Kerschen

Hernández²,

Zogg³

et al. 2010

J. Clin. Invest.

104

View full text Add to dashboard Cite

show abstract

“…However, PC has also been regarded as a link between coagulation and inflammation, 17 because uncontrolled coagulation results in thrombosis, as well as promotion of cellular proliferation and an inflammatory response. 18 Although increased neutrophil infiltration was observed in PC Ϫ/Ϫ E18.5dpc embryos, an inflammatory-related cause of death was not thoroughly explored.…”

Section: Discussionmentioning

confidence: 99%

The Characterization of Mice with a Targeted Combined Deficiency of Protein C and Factor XI

Chan

Ganopolsky

Cornelissen

et al. 2001

The American Journal of Pathology

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“…Other studies have shown that blocking the binding of activated protein C to EPCR did not affect the inhibition of TNF-␣ production by activated protein C in LPS-stimulated human monocytes (11). It is also possible that there may be an alternative activated protein C-binding receptor on the surface of monocytes (51). Using Ca 2ϩ -free conditions (which prevents activated protein C-EPCR interactions) (52) or mAbs that block activated protein C-EPCR interactions (53), we observed that recombinant activated protein C retained the ability to bind to the monocyte cell surface (unpublished observations).…”

Section: Figurementioning

confidence: 96%

Activated Protein C Up-Regulates IL-10 and Inhibits Tissue Factor in Blood Monocytes

Toltl¹,

Beaudin

Liaw

2008

The Journal of Immunology

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The protective effect of recombinant activated protein C therapy in patients with severe sepsis likely reflects the ability of recombinant activated protein C to modulate multiple pathways implicated in sepsis pathophysiology. In this study, we examined the effects of recombinant activated protein C on the anti-inflammatory cytokine IL-10 and on the procoagulant molecule tissue factor (TF) in LPS-challenged blood monocytes. Treatment of LPS-stimulated monocytes with recombinant activated protein C resulted in an up-regulation of IL-10 protein production and mRNA synthesis. The up-regulation of IL-10 required the serine protease activity of recombinant activated protein C and was dependent on protease-activated receptor-1, but was independent of the endothelial protein C receptor. At the intracellular level, p38 MAPK activation was required for recombinant activated protein C-mediated up-regulation of IL-10. We further observed that incubation of LPS-stimulated monocytes with recombinant activated protein C down-regulated TF Ag and activity levels. This anticoagulant effect of recombinant activated protein C was dependent on IL-10 since neutralization of endogenously produced IL-10 abrogated the effect. In patients with severe sepsis, plasma IL-10 levels were markedly higher in those treated with recombinant activated protein C than in those who did not receive recombinant activated protein C. This study reveals novel regulatory functions of recombinant activated protein C, specifically the up-regulation of IL-10 and the inhibition of TF activity in monocytes. Our data further suggest that these activities of recombinant activated protein C are directly linked: the recombinant activated protein C-mediated up-regulation of IL-10 reduces TF in circulating monocytes.

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Binding of Activated Protein C to a Specific Receptor on Human Mononuclear Phagocytes Inhibits Intracellular Calcium Signaling and Monocyte-Dependent Proliferative Responses1,2

Cited by 122 publications

References 0 publications

Activated protein C targets CD8+ dendritic cells to reduce the mortality of endotoxemia in mice

Activated protein C targets CD8+ dendritic cells to reduce the mortality of endotoxemia in mice

The Characterization of Mice with a Targeted Combined Deficiency of Protein C and Factor XI

Activated Protein C Up-Regulates IL-10 and Inhibits Tissue Factor in Blood Monocytes

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