PMID- 21228323
OWN - NLM
STAT- MEDLINE
DCOM- 20110520
LR  - 20200930
IS  - 1522-1563 (Electronic)
IS  - 0363-6143 (Linking)
VI  - 300
IP  - 4
DP  - 2011 Apr
TI  - Protective cross talk between activated protein C and TNF signaling in vascular 
      endothelial cells: implication of EPCR, noncanonical NF-kappaB, and ERK1/2 MAP 
      kinases.
PG  - C833-42
LID - 10.1152/ajpcell.00003.2010 [doi]
AB  - Activated protein C (APC) is a natural anticoagulant protease that displays 
      cytoprotective and antiinflammatory activities and has been demonstrated to 
      reduce mortality of patients with severe sepsis. However, APC signaling is not 
      fully understood. This study further investigated the antiinflammatory effects of 
      APC in vascular endothelial cells (EC) and examined the cross talk between APC 
      and TNF signaling. Analysis of the regulatory mechanisms mediated by APC on 
      vascular human EC shows that APC impairs TNF signaling by triggering a preemptive 
      activation of intracellular pathways. We found that APC signaling causes a 
      moderate but significant induction of cell adhesion molecules (CAMs) including 
      VCAM-1 at mRNA and protein levels. Activation of the noncanonical NF-kappaB and 
      ERK1/2 are both pivotal to APC signaling leading to VCAM-1 expression. APC 
      upregulates TNF receptor-associated factor 2 (TRAF2) and phosphorylates NF-kappaB p65 
      at Ser276 and Ser536 independently of IkappaB degradation. The ultimate protective 
      antiinflammatory effect of APC in response to TNF is associated with a sustained 
      activation of ERK1/2 and Akt while phosphorylation of NF-kappaB p65 is precluded. 
      Inhibitors of ERK (PD98059 and U0126) abolish the antiinflammatory signal 
      mediated by APC. Blocking antibodies and silencing assays also suggest that, in 
      EC, protease-activated receptor 1 and endothelial protein C receptor (EPCR) both 
      conduct ERK activation and VCAM-1 induction in response to APC. To conclude, APC 
      protects EC by attenuating CAM expression during inflammation. APC engages a 
      regulatory cross talk involving EPCR, ERK, and NF-kappaB that impairs TNF signaling.
FAU - Guitton, Christophe
AU  - Guitton C
AD  - Institut national de la sante et de la recherche medicale, Nantes, France.
FAU - Cottereau, Alice
AU  - Cottereau A
FAU - Gerard, Nathalie
AU  - Gerard N
FAU - Quillard, Thibaut
AU  - Quillard T
FAU - Chauveau, Annabelle
AU  - Chauveau A
FAU - Devalliere, Julie
AU  - Devalliere J
FAU - Tonnerre, Pierre
AU  - Tonnerre P
FAU - Charreau, Beatrice
AU  - Charreau B
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110112
PL  - United States
TA  - Am J Physiol Cell Physiol
JT  - American journal of physiology. Cell physiology
JID - 100901225
RN  - 0 (Antigens, CD)
RN  - 0 (E-Selectin)
RN  - 0 (Endothelial Protein C Receptor)
RN  - 0 (NF-kappa B)
RN  - 0 (PROCR protein, human)
RN  - 0 (Protein C)
RN  - 0 (Receptor, PAR-1)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (Vascular Cell Adhesion Molecule-1)
RN  - 126547-89-5 (Intercellular Adhesion Molecule-1)
RN  - EC 2.7.11.24 (MAPK1 protein, human)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
SB  - IM
MH  - Animals
MH  - Antigens, CD/genetics/metabolism
MH  - Cells, Cultured
MH  - E-Selectin/metabolism
MH  - Endothelial Cells/cytology/*physiology
MH  - Endothelial Protein C Receptor
MH  - Humans
MH  - Intercellular Adhesion Molecule-1/metabolism
MH  - Mitogen-Activated Protein Kinase 1/genetics/*metabolism
MH  - Mitogen-Activated Protein Kinase 3/genetics/*metabolism
MH  - NF-kappa B/*metabolism
MH  - Protein C/*metabolism
MH  - Receptor, PAR-1/genetics/metabolism
MH  - Receptors, Cell Surface/genetics/metabolism
MH  - Signal Transduction/*physiology
MH  - Tumor Necrosis Factor-alpha/genetics/*metabolism
MH  - Vascular Cell Adhesion Molecule-1/genetics/metabolism
EDAT- 2011/01/14 06:00
MHDA- 2011/05/21 06:00
CRDT- 2011/01/14 06:00
PHST- 2011/01/14 06:00 [entrez]
PHST- 2011/01/14 06:00 [pubmed]
PHST- 2011/05/21 06:00 [medline]
AID - ajpcell.00003.2010 [pii]
AID - 10.1152/ajpcell.00003.2010 [doi]
PST - ppublish
SO  - Am J Physiol Cell Physiol. 2011 Apr;300(4):C833-42. doi: 
      10.1152/ajpcell.00003.2010. Epub 2011 Jan 12.