Abstract
Objective: Serum amyloid A (SAA) is an apolipoprotein transported within the high density lipoprotein (HDL) in plasma. The SAA plasma levels increase during inflammatory conditions, e.g., in patients with chronic renal failure (CRF). The SAA-dependent reduction in anti-inflammatory condition of HDL and its pro-inflammatory response in smooth muscle cells was shown previously. The aim of this study was to investigate the signaling pathways of SAA in macrophages and therefore its influence on inflammatory vascular disease. Design and method: THP-1 (human) monocytes were activated via PMA to macrophages and used for monocyte chemoattractant protein-1 (MCP-1) experiments. Murine RAW264.7 monocytes/macrophages were used for nitrite experiments. MCP-1 production was detected by Luminex™ technology. Nitrite production were measured via Griess Assay. Cell viability was determined via MTS assay. Results: SAA accumulates in plasma of patients during conditions of CRF. Whereas there is only a slight increase within CRF stage 1 and 2, the plasma level of SAA further increase during CRF stage 3 to 5. Beside the pro-inflammatory potential of SAA to induce MCP-1 in vascular smooth muscle cells, it also induces MCP-1 secretion in human THP-1 macrophages in a dose-dependent manner. In addition, the production of nitrite was dose-dependently increased in murine RAW264.7 cells. Both, MCP-1 and nitrite production induced by SAA were regulated via TLR and SR-BI receptor activation. The TLR2/4 antagonist oxPAPC and the SR-BI antagonist BLT-1 diminished the SAA-induced MCP-1 and nitrite production. The activation of FPR2 seems not to be involved in the signaling pathway in macrophages after SAA stimulation in that experimental condition. Stimulation with receptor agonists confirmed these findings. The concentration used for agonists/antagonists had no significant influence on cell viability of macrophages. Conclusions: In conclusion, the pro-inflammatory reaction of SAA in macrophages in vitro depends on TLR2/4 and SR-BI activation. The accumulation of SAA plasma levels during CRF may substantially contribute to the increased cardiovascular risk of these patients.
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