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Serum amyloid A induces monocyte tissue factor
Hong Cai1, Changjie Song, Ikuko Endoh
1Inflammatory Diseases Research Unit, School of Medical Sciences, University of New South Wales, Sydney, Australia.
Abstract:
C-reactive protein (CRP) and serum amyloid A (SAA) increase in the blood of patients with inflammatory conditions and CRP-induced monocyte tissue factor (TF) may contribute to inflammation-associated thrombosis. This study demonstrates that SAA is a potent and rapid inducer of human monocyte TF. SAA induced TF mRNA in PBMC within 30 min and optimal procoagulant activity within 4 h, whereas CRP (25 mug/ml)-induced activity was minimal at this time. Unlike CRP, SAA did not synergize with LPS. Procoagulant activity was inhibited by anti-TF and was dependent on factors VII and X, and TF Ag levels were elevated on CD14(+) monocytes. Responses were optimal with lymphocytes, although these were not obligatory. Inhibitor studies indicate activation of NF-kappaB through the ERK1/2 and p38 MAPK pathways; the cyclo-oxygenase pathway was not involved. SAA-induced TF was partially inhibited by high-density lipoprotein, but not by low-density lipoprotein or by apolipoprotein A-I. SAA is a ligand for the receptor for advanced glycation end products (RAGE), and TF generation was suppressed by approximately 50% by a RAGE competitor, soluble RAGE, and by approximately 85% by anti-RAGE IgG. However, another RAGE ligand, high mobility group box-1 protein, capable of inducing monocyte chemotactic protein-1 mRNA in 2 h, did not induce TF within 24 h. Cross-linking studies confirmed SAA binding to soluble RAGE. Elevated SAA is a marker of disease activity in patients with rheumatoid arthritis, and PBMC from patients with rheumatoid arthritis were more sensitive to SAA than normals, suggesting a new link between inflammation and thrombosis.
Insights
Serum amyloid A (SAA) rapidly induces human monocyte tissue factor (TF) production, a key factor in inflammation-associated thrombosis. This contrasts with C-reactive protein (CRP) and highlights SAA
Area of Science:
- Immunology
- Molecular Biology
- Hematology
Background:
- Inflammatory conditions elevate C-reactive protein (CRP) and serum amyloid A (SAA) levels.
- CRP-induced monocyte tissue factor (TF) is implicated in inflammation-associated thrombosis.
- The specific role of SAA in inducing TF and its contribution to thrombosis require further elucidation.
Purpose of the Study:
- To investigate the capacity of serum amyloid A (SAA) to induce tissue factor (TF) in human monocytes.
- To compare the TF-inducing potency and kinetics of SAA with C-reactive protein (CRP).
- To elucidate the molecular pathways and receptors involved in SAA-mediated TF induction.
Main Methods:
- Measurement of TF mRNA and procoagulant activity in peripheral blood mononuclear cells (PBMCs) stimulated with SAA and CRP.
- Assessment of TF dependency on coagulation factors VII and X, and TF antigen levels on CD14+ monocytes.
- Inhibitor studies targeting NF-kappaB, MAPK pathways, cyclo-oxygenase, and RAGE.
- Analysis of SAA binding to RAGE and the effect of RAGE competitors.
Main Results:
- SAA rapidly induced TF mRNA and procoagulant activity in human monocytes, significantly faster and more potently than CRP.
- TF induction by SAA involved NF-kappaB activation via ERK1/2 and p38 MAPK pathways, independent of cyclo-oxygenase.
- SAA-induced TF generation was partially inhibited by high-density lipoprotein and significantly suppressed by RAGE blockade.
- PBMCs from rheumatoid arthritis patients showed heightened sensitivity to SAA-induced TF compared to healthy individuals.
Conclusions:
- SAA is a potent and rapid inducer of human monocyte tissue factor, suggesting a significant role in inflammation-associated thrombosis.
- The SAA-RAGE axis is crucial for TF induction, offering potential therapeutic targets.
- Increased SAA sensitivity in rheumatoid arthritis patients links inflammation directly to thrombotic risk via TF induction.
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