The synthesis of acute-phase protein serum amyloid A (SAA) is largely regulated by inflammation- associated cytokines and a high concentration of circulating SAA may represent an ideal marker for acute and chronic inflammatory diseases. However, SAA is also synthesized in extrahepatic tissues, e.g. human carcinoma metastases and cancer cell lines. An increasing body of in vitro data supports the concept of involvement of SAA in carcinogenesis and neoplastic diseases. Accumulating evidence suggests that SAA might be included in a group of biomarkers to detect a pattern of physiological events that reflect the growth of malignancy and host response. This review is meant to provide a broad overview of the many ways that SAA could contribute to tumour development, and accelerate tumour progression and metastasis, and to gain a better understanding of this acute-phase reactant as a possible link between chronic inflammation and neoplasia.

Objective-Myeloperoxidase, a heme enzyme that is present and active in human atherosclerotic lesions, provides a source for the generation of proinflammatory chlorinated reactants contributing to endothelial dysfunction. Modification of high-density lipoprotein (HDL) by hypochlorous acid/hypochlorite (HOCl/Oce Ϫ )-generated in vivo by the myeloperoxidase-hydrogen peroxide-chloride system of activated phagocytes-forms a proatherogenic lipoprotein particle that binds to and is internalized by endothelial cells. Methods and Results-Here we show that HDL, modified with physiologically relevant HOCl concentrations, attenuates the expression and activity of vasculoprotective endothelial nitric oxide synthase. HOCl-HDL promotes dislocalization of endothelial nitric oxide synthase from the plasma membrane and perinuclear location of human umbilical venous endothelial cells. We could identify 2-chlorohexadecanal as the active component mediating this inhibitory activity. This chlorinated fatty aldehyde is formed during HOCl-mediated oxidative cleavage of HDL-associated plasmalogen. Conclusion-2-Chlorohexadecanal, produced by the myeloperoxidase-hydrogen peroxide-chloride system of activated phagocytes may act as a mediator of vascular injury associated with ischemia-reperfusion injury, glomerulosclerosis, and atherosclerosis. Key Words: myeloperoxidase Ⅲ 2-chlorinated fatty aldehyde Ⅲ atherosclerosis Ⅲ modified lipids Ⅲ glomerulosclerosis Ⅲ neutrophils A nimal experimentation and clinical studies have provided convincing evidence that the known risk factors for cardiovascular disease can elicit a localized inflammatory response in the vasculature. The changes are most pronounced in endothelial cells and include oxidative stress, increased activation of endothelial signaling pathways, and the consequent adhesion, activation, and degranulation of leukocytes. The myeloperoxidase (MPO)-hydrogen peroxidesystem of stimulated leukocytes, primarily neutrophils, generates hypochlorous acid/hypochlorite (HOCl/Oce Ϫ ), a potent bacterial oxidant in vivo. 1 MPO and HOCl are emerging as critical modulators of vascular injury by promoting inflammatory arterial pathology and subsequent formation of mature plaques. MPO is present and active in human lesion material. 2 HOCl reacts with a wide range of biological substrates, including antioxidants, amines, sulfides, nucleotides, DNA, lipids, and (lipo)proteins. [3][4][5] HOCl-modified (lipo)proteins are present in human 6 -8 and rabbit lesions, 9,10 and disease stage-dependent accumulation of HOCl-modified (lipo)proteins has been reported. 7 Elevated levels of plasma high-density lipoprotein (HDL) protect against atherosclerotic vascular disease. A broad spectrum of potent antioxidant and anti-inflammatory activities has been ascribed to native HDL. 11,12 However, oxidation/modification by HOCl alters the physicochemical and metabolic properties of anti-atherogenic HDL. [13][14][15] In vivo, apolipoprotein A-I, the major apolipoprotein of HDL, represents a selective target for MPO-catalyz...

Although the liver is the primary site of cytokine-mediated expression of acute-phase serum amyloid A (SAA) protein, extrahepatic production has also been reported. Besides its role in amyloidosis and lipid homeostasis during the acute-phase, SAA has recently been assumed to contribute to bone and cartilage destruction. However, expression of SAA in human osteogenic tissue has not been studied. Therefore, we first show that SAA1 (coding for the major SAA isoform) but not SAA2 transcripts are expressed in human trabecular and cortical bone fractions and bone marrow. Next, we show expression of (i) IL-1, IL-6, and TNF receptor transcripts; (ii) the human homolog of SAA-activating factor-1 (SAF-1, a transcription factor involved in cytokine-mediated induction of SAA genes); and (iii) SAA1/2 transcripts in non-differentiated and, to a higher extent, in osteoblast-like differentiated human mesenchymal stem cells. Third, we provide evidence that human osteoblast-like cells of tumor origin (MG-63 and SAOS-2) express SAF-1 under basal conditions. SAA1/2 transcripts are expressed under basal conditions (SAOS-2) and cytokine-mediated conditions (MG-63 and SAOS-2). RT-PCR, Western blot analysis, and immunofluorescence technique confirmed cytokine-mediated expression of SAA on RNA and

The placenta comprises a highly specialized trophoblast layer, which arises from the embryo and differentiates during embryonic development to perform specialized functions, e.g., synthesis of pregnancy-associated hormones, growth factors and cytokines. As there is no evidence of maternal acute-phase protein transplacental transfer and trophoblast plays an important role in regulating immune responses at the feto-maternal interface, the expression of acute-phase serum amyloid A (A-SAA) was investigated in human first trimester trophoblast and trophoblast-like JAR and Jeg-3 choriocarcinoma cells. We here show expression of cytokine receptors and cytokine-dependent induction of A-SAA in JAR and Jeg-3 cells. While interleukin1a/b is a major agonist for A-SAA expression in JAR, tumor necrosis factor-a is the predominant agonist in Jeg-3. First trimester trophoblast and JAR/Jeg-3 cells further express the human homolog of SAA-activating factor-1, a transcription factor involved in cytokine-mediated induction of A-SAA genes. A-SAA1 and A-SAA2 transcripts were increased in first trimester trophoblast during pregnancy weeks 10 and 12 suggesting that A-SAA plays a role during early fetal development.

Background and purpose: Endothelins (ETs) and their G protein-coupled receptors exert key physiological functions during normal and aberrant placental development. Trophoblast cells mediate the contact between the embryo and the mother, by establishing a transient organ, the placenta. Choriocarcinoma cells display many of the biochemical and morphological characteristics of in utero invasive trophoblast cells and may therefore be used as a suitable model to study epithelial tumour progression of foetal-derived cells. Experimental approach: The present study aimed at investigating ET receptor-mediated activation of the mitogen-activated protein kinase (MAPK) pathway in human choriocarcinoma. Key results: Both JAR and Jeg-3 choriocarcinoma cell lines expressed ET receptor subtype B (ET B ) but not ET A receptor transcripts. ET B receptor engagement by ET-1 and ET-3 resulted in a similar time-and concentration-dependent phosphorylation of p42/44 MAPK, also known as extracellular regulated kinase 1/2. Using specific pharmacological antagonists/inhibitors, we showed that ET-1/-3-mediated signal transduction by the ET B receptor is transmitted via G i -and G q -dependent pathways through activation of the Src (G i ) and protein kinase C (G q ) axis that converge at Ras/Raf, leading to downstream activation of p42/44. On a functional level, ET B engagement and subsequent phosphorylation of p42/44 resulted in enhanced transcription of the immediate early response genes c-fos and c-jun, a process commonly assumed to be mediated by the ET A receptor, and increased cell growth and relative cell area. Conclusions and implications: As human choriocarcinoma cells secrete ETs, pharmacological antagonism of ETs and/or ET B receptor-mediated signal transduction could represent a likely target therapy for choriocarcinoma.