The complement component C5a induces the expression of plasminogen activator inhibitor-1 in human macrophages via NF-κB activation

Kastl, Stefan P.; Speidl, Walter S.; Kaun, Christoph; Rega, Gersina; Assadian, Afshin; Weiss, Thomas W.; Valent, Peter; Hagmueller, Georg W.; Maurer, Gerald; Huber, Kurt; Wojta, Johann

doi:10.1111/j.1538-7836.2006.02046.x

Cited by 73 publications

(50 citation statements)

References 42 publications

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“…6D). These results clearly demonstrate the effect of C5a stimulation in activating NF-B signaling in DCs and also suggest that C5a and LPS have a synergistic effect on NF-B activation in DCs, which are in agreement with the previous findings that C5a alone, or C5a cooperating with LPS, activates NF-B signaling in macrophages (20,32).…”

Section: C5a Stimulation Activates Nf-b Signaling In Dcssupporting

confidence: 82%

Dendritic Cell Function in Allostimulation Is Modulated by C5aR Signaling

Peng

Wang

et al. 2009

The Journal of Immunology

107

103

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Regulation of T cell immunity by C5a has been suggested from recent studies. However, the underlying mechanisms, particularly the involved cells and biochemical basis, are not well defined. In this study, the direct modulation of dendritic cell (DC) activation and its function in T cell stimulation by C5a-C5aR interaction and the involved signaling pathways were investigated. We show that DCs from C5aR−/− mice and normal DCs treated with C5aR antagonist have less-activated phenotype characterized with increased IL-10 and decreased IL-12p70 production in response to LPS stimulation, lowered surface expression of MHC class II, B7.2, and consequently have reduced capacity to stimulate allospecific T cells. Conversely, C5a stimulation up-regulates DC activation and its function in allostimulation. Furthermore, stimulation of C5aR mediates the inhibition of cAMP production and protein kinase A activity and is involved in activation of PI3K/AKT and NF-κB signaling in DCs. These results demonstrate that C5a acts directly on C5aR expressed on DCs resulting in the cell activation and subsequently enhances its capacity for allospecific T cell stimulation. It also suggests that NF-κB signaling induced by down-regulation of cAMP/ protein kinase A pathway and up-regulation of PI3K/AKT pathway following C5a stimulation may contribute to up-regulation of DC function.

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Section: C5a Stimulation Activates Nf-b Signaling In Dcssupporting

confidence: 82%

Dendritic Cell Function in Allostimulation Is Modulated by C5aR Signaling

Peng

Wang

et al. 2009

The Journal of Immunology

107

103

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“…16 ECs and macrophages 23 in atherosclerotic lesions were found to express C5aR, and the effect of C5a has been investigated. 6 After vascular injury, VSMCs show increased proliferation, migration, and synthetic capacity and play a critical role in vascular remodeling.…”

Section: C5ar Expression In Mouse Neointimal Plaque Tissue and In Vsmmentioning

confidence: 99%

C5a Receptor Targeting in Neointima Formation After Arterial Injury in Atherosclerosis-Prone Mice

et al. 2010

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Background-Receptor binding of complement C5a leads to proinflammatory activation of many cell types, but the role of receptor-mediated action during arterial remodeling after injury has not been studied. In the present study, we examined the contribution of the C5a receptor (C5aR) to neointima formation in apolipoprotein E-deficient mice employing a C5aR antagonist (C5aRA) and a C5aR-blocking monoclonal antibody. Methods and Results-Mice fed an atherogenic diet were subjected to wire-induced endothelial denudation of the carotid artery and treated with C5aRA and anti-C5aR-blocking monoclonal antibody or vehicle control. Compared with controls, neointima formation was significantly reduced in mice receiving C5aRA or anti-C5aR-blocking monoclonal antibody for 1 week but not for 3 weeks, attributable to an increased content of vascular smooth muscle cells, whereas a marked decrease in monocyte and neutrophil content was associated with reduced vascular cell adhesion molecule-1. As assessed by immunohistochemistry, reverse transcription polymerase chain reaction, and flow cytometry, C5aR was expressed in lesional and cultured vascular smooth muscle cells, upregulated by injury or tumor necrosis factor-␣, and reduced by C5aRA. Plasma levels and neointimal plasminogen activator inhibitor-1 peaked 1 week after injury and were downregulated in C5aRA-treated mice. In vitro, C5a induced plasminogen activator inhibitor-1 expression in endothelial cells and vascular smooth muscle cells in a C5aRA-dependent manner, possibly accounting for higher vascular smooth muscle cell immigration. Conclusions-One-week treatment with C5aRA or anti-C5aR-blocking monoclonal antibody limited neointimal hyperplasia and inflammatory cell content and was associated with reduced vascular cell adhesion molecule-1 expression. 3 and adverse cardiovascular events have been correlated with C5a plasma levels. 4 C5a is a potent soluble anaphylotoxic and chemotactic inflammatory mediator promoting the recruitment and activation of neutrophils and monocytes. 5 C5a specifically binds to its receptor C5aR (also named CD88), a rhodopsin-type receptor expressed in various cell types. In addition to immune cells (neutrophils, eosinophils, basophils, monocytes/macrophages, mast cells, dendritic cells, and T cells), C5aR has also been detected in nonimmune cells, including neuronal and endothelial cells (ECs), and in different tissues (lung, kidney, liver, spleen, intestine, skin, and heart). 6 Binding of C5a to C5aR leads to cellular activation, including adhesion and chemotaxis. 7 Enhanced surface and messenger RNA (mRNA) expression of C5aR was found in microvascular ECs after exposure to lipopolysaccharide, interferon-␥, and interleukin-6, concomitant with an upregulation of macrophage-inflammatory protein-2/ CXCL2 and macrophage chemoattractant protein-1/CCL2. 8 Stimulation of ECs with C5a increases the gene expression of adhesion molecules, 9,10 cytokines, chemokines, and related receptors. 9,11 Clinical Perspective on p 1036In C5aR-deficient mice, IgG...

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“…This study has limitations, including the fact that we only measured PAI-1 mRNA in mononuclear cells, which may not reflect gene expression in other tissues. Previous studies have shown that other cell types, in addition to monocytes/macrophages, produce PAI-1 (28,29). However, sequential sampling of peripheral blood is the only practical method available at present to serially test gene expression over a short interval in a dynamic environment such as exists after cardiac surgery.…”

Section: Discussionmentioning

confidence: 99%

Coagulopathy After Cardiac Surgery May Be Influenced by a Functional Plasminogen Activator Inhibitor Polymorphism

Duggan

O'Dwyer²,

Caraher³

et al. 2007

Anesthesia &Amp; Analgesia

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BACKGROUND: Cytokine-mediated inflammation and coagulopathy may occur after cardiac surgery. In this study we investigated the temporal pattern of plasminogen activator inhibitor-1 (PAI-1) gene expression after cardiac surgery and its relation with PAI genotype, and obtained preliminary data regarding its relation to perioperative morbidity. METHODS: The relative change in PAI-1 mRNA 1, 6, and 24 h after cardiopulmonary bypass (CPB) was measured from mononuclear cells in 82 patients undergoing elective cardiac surgery. DNA was analyzed for carriage of the 4G/5G PAI-1 polymorphism. RESULTS: PAI-1 gene expression decreased after CPB in all patients. A larger reduction in PAI-1 gene expression was observed in homozygous carriers of the 5G allele. Homozygous carriers of the 5G allele were also more likely to receive transfusion of coagulation blood products. There was no relation between change in PAI-1 gene expression and duration of CPB. CONCLUSIONS: PAI-1 gene expression decreased over time after CPB. We found a link between PAI-1 genotype, PAI gene expression, and transfusion of coagulation products after cardiac surgery.

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The complement component C5a induces the expression of plasminogen activator inhibitor-1 in human macrophages via NF-κB activation

Cited by 73 publications

References 42 publications

Dendritic Cell Function in Allostimulation Is Modulated by C5aR Signaling

Dendritic Cell Function in Allostimulation Is Modulated by C5aR Signaling

C5a Receptor Targeting in Neointima Formation After Arterial Injury in Atherosclerosis-Prone Mice

Coagulopathy After Cardiac Surgery May Be Influenced by a Functional Plasminogen Activator Inhibitor Polymorphism

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