Activated Protein C Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor-α Production by Inhibiting Activation of both Nuclear Factor-κB and Activator Protein-1 in Human Monocytes

Yüksel, Mustafa; Okajima, Kenji; Uchiba, Mitsuhiro; Horiuchi, Seikoh; Okabe, Hiroaki

doi:10.1055/s-0037-1613197

Cited by 170 publications

(108 citation statements)

References 40 publications

Supporting

Mentioning

103

Contrasting

Unclassified

Order By: Relevance

“…Furthermore, recent reports demonstrate that recombinant activated protein C can induce a cell signaling response via ERK activation through a PAR-1/S1P1-dependent, but EPCR-independent, mechanism (50). 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).…”

Section: Figurementioning

confidence: 97%

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

Toltl¹,

Beaudin

Liaw

2008

The Journal of Immunology

View full text Add to dashboard Cite

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.

show abstract

Section: Figurementioning

confidence: 97%

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

Toltl¹,

Beaudin

Liaw

2008

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…sepsis receiving recombinant activated protein C contained reduced levels of IL-6 (4). In vitro studies have also revealed that 360 nM and 3.6 M activated protein C inhibited TNF-␣ secretion by CD14 ϩ peripheral monocytes and by THP-1 cells, respectively (14,15). However, the regulated secretion of numerous other cytokines by activated protein C-treated monocytes has not been documented to date.…”

Section: Figurementioning

confidence: 99%

“…More recently, activated protein C has been shown to inhibit inflammation (13)(14)(15)(16)(17)(18), apoptosis (19 -22), and to prevent increases in vascular permeability (23,24). With respect to its antiinflammatory properties, activated protein C has been shown to down-regulate the production of TNF by monocytes (13)(14)(15) and to suppress expression of leukocyte adhesion molecules in endothelial cells (16), presumably by inhibiting NF-B nuclear translocation (14) and/or down-regulating the transcription of NF-B subunits (16).…”

mentioning

confidence: 99%

“…With respect to its antiinflammatory properties, activated protein C has been shown to down-regulate the production of TNF by monocytes (13)(14)(15) and to suppress expression of leukocyte adhesion molecules in endothelial cells (16), presumably by inhibiting NF-B nuclear translocation (14) and/or down-regulating the transcription of NF-B subunits (16). In animals challenged with endotoxin, activated protein C inhibited the production of proinflammatory cytokines (17,18) and inhibited leukocyte accumulation in injured tissue (25).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Modulation of Monocyte Function by Activated Protein C, a Natural Anticoagulant

Stephenson¹,

Toltl²,

Beaudin

et al. 2006

The Journal of Immunology

View full text Add to dashboard Cite

Activated protein C is the first effective biological therapy for the treatment of severe sepsis. Although activated protein C is well established as a physiological anticoagulant, emerging data suggest that it also exerts anti-inflammatory and antiapoptotic effects. In this study, we investigated the ability of activated protein C to modulate monocyte apoptosis, inflammation, phagocytosis, and adhesion. Using the immortalized human monocytic cell line THP-1, we demonstrated that activated protein C inhibited camptothecin-induced apoptosis in a dose-dependent manner. The antiapoptotic effect of activated protein C requires its serine protease domain and is dependent on the endothelial cell protein C receptor and protease-activated receptor-1. In primary blood monocytes from healthy individuals, activated protein C inhibited spontaneous apoptosis. With respect to inflammation, activated protein C inhibited the production of TNF, IL-1β, IL-6, and IL-8 by LPS-stimulated THP-1 cells. Activated protein C did not influence the phagocytic internalization of Gram-negative and Gram-positive bioparticles by THP-1 cells or by primary blood monocytes. Activated protein C also did not affect the expression of adhesion molecules by LPS-stimulated blood monocytes nor the ability of monocytes to adhere to LPS-stimulated endothelial cells. We hypothesize that the protective effect of activated protein C in sepsis reflects, in part, its ability to prolong monocyte survival in a manner that selectively inhibits inflammatory cytokine production while maintaining phagocytosis and adherence capabilities, thereby promoting antimicrobial properties while limiting tissue damage.

show abstract

“…in the WNC group could be the consequence of an acute phase response induced by the infectious stimulus. This response could be favourable for the host, considering its anti-inflammatory properties, as reported by Yuksel et al (2002). However, no significant differences in the levels of PC were observed in the animals that received L. casei.…”

Section: Discussionmentioning

confidence: 61%

Modulation of the immuno-coagulative response in a pneumococcal infection in malnourished mice nasally treated with Lactobacillus casei

Zelaya

Laiño

Haro

et al. 2013

Journal of Medical Microbiology

View full text Add to dashboard Cite

We studied the systemic effects of the intranasal administration of Lactobacillus casei on the immuno-coagulative response in pneumoccocal infection in immunocompromised mice. Weaned mice consumed a protein-free diet (PFD) for 21 days and were therefore malnourished. Malnourished mice were fed a balanced conventional diet (BCD) for 7 days (BCD group) or a BCD for 7 days with nasal administration of viable L. casei on days 6 and 7 (BCD+LcN group). The malnourished control mice (MNC) received a PFD, whereas the well-nourished control mice (WNC) continually consumed a BCD. At the end of the treatment period, the mice were infected with Streptococcus pneumoniae. At different times after infection, we analysed the following parameters: global coagulation system, activation of coagulation, coagulation inhibitors, platelet count, leukocyte count and myeloperoxidase (MPO) activity, total proteins, albumin and acute phase proteins (APPs). The MNC group showed greater impairment in the coagulation tests and an increase in the positive APPs. These parameters were normalized by the L. casei treatment. However, the number of leukocytes, decreased by malnutrition, was improved only by the administration of L. casei. After infection, the BCD+LcN group showed similar results to those of the WNC group for most of the haemostatic parameters. The BCD+LcN group did not show significant variations in the prothrombin time or in the level of anticoagulant protein C, but showed higher levels of fibrinogen, platelets, albumin, leukocytes and MPO activity compared with the different experimental groups. The intranasal administration of L. casei was effective in modulating the pro-inflammatory aspects of coagulation without affecting coagulation itself.

show abstract

Activated Protein C Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor-α Production by Inhibiting Activation of both Nuclear Factor-κB and Activator Protein-1 in Human Monocytes

Cited by 170 publications

References 40 publications

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

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

Modulation of Monocyte Function by Activated Protein C, a Natural Anticoagulant

Modulation of the immuno-coagulative response in a pneumococcal infection in malnourished mice nasally treated with Lactobacillus casei

Contact Info

Product

Resources

About