Cytokine-induced differential expression of serum amyloid A genes in fetal and neonatal rabbits

Abstract

SUMMARYSerum amyloid A (SAA) is an acute-phase plasma protein which increases 100-to 1000-fold in response to inflammatory stimuli. In this study pregnant rabbits were subjected to laparotomy and their fetuses were injected with lipopolysaccharide (LPS) or various cytokines. Newborn rabbits were likewise stimulated. Hepatic SAA mRNA was studied using Northern blot analyses and scanning densitometry. In vitro derived RNA was used as standard for quantitative mRNA analyses. Cytokine concentrations in amniotic fluid and serum were analysed by biological assays. Fetal rabbits responded to cytokine stimulation by increased hepatic SAA mRNA expression, both during late gestation and in the early neonatal period. However, differences in dose-responses, kinetics and mRNA concentrations were seen dependent on gestational age. IL-1 and tumour necrosis factor (TNF) induced hepatic accumulation of both SAA1, SAA2 and SAA3, while only SAA1 and SAA2 mRNA accumulation was seen after IL-6 stimulation. High levels of IL-1 and TNF found in amniotic fluid from LPS-stimulated fetal rabbits corresponded with high levels in fetal, but not in maternal, serum. High levels of IL-1 and TNF, but no IL-6, were seen in newborn control sera and in adult serum 1 day after a normal delivery. The study details the complexity of the cytokine-induced in vivo response of SAA mRNA in fetal and neonatal rabbits.

Regulation of Extrahepatic Apolipoprotein Serum Amyloid A (ApoSAA) Gene Expression by Interleukin‐1α Alone: Synthesis and Secretion of ApoSAA by Cultured Aortic Smooth Muscle Cells

“…In addition, the neonatal cells used in this report have been likened to the proliferative atherosclerotic phenotype [23,38,39] which may respond differently than cells from an older individual. Once again, it is noteworthy that the neonatal liver expressed apoSAA 3 mRNA by RT-PCR, and this is consistent with the findings of Rygg [33]. Future studies are likely to elucidate the reason for the differences; nonetheless, this report is the first to show that primary aortic SMCs are capable of synthesizing and secreting the A-apoSAA protein, suggesting a likely source of its accumulation in atherosclerosis.…”

“…However, in response to IL-1a, these levels are elevated in a time dependent and dose responsive fashion. Interestingly, IL-6 does not appear to contribute significantly to SMC apoSAA 3 synthesis; this is particularly intriguing in light of in vivo studies in which IL-6 did not induce apoSAA 3 gene expression in fetal and neonatal rabbit liver [33]. Likewise, IL-6 was shown to have little effect on the IL-1a induced human A-apoSAA mRNA expression in the cultured human endothelial cell line, ECV304 [34].…”

Serum amyloid A and high‐density lipoprotein cholesterol: serum markers of inflammation in sarcoidosis and other systemic disorders

“…Triggered by inflammation after stimulation of hepatocytes by lymphokine‐mediated processes and particularly activated monocytes and macrophages, the concentrations of SAA may increase during the acute‐phase reaction to levels 1000‐fold greater than those found in the noninflammatory state, resembling a classic positive acute‐phase reactant [40](Table 3). Different cytokines have been shown to affect SAA hepatic synthesis at the transcriptional level, principally the IL‐1 and IL‐6 type cytokines [41,42]. Measurements of SAA are of value in the assessment of activity and response to therapy of several inflammatory diseases [43–45].…”

Acute‐phase proteins in perinatal human plasma

“…We report in this paper that these proteins become electrophoretically detectable in newborn serum during infections. substantiated by experimental data showing that lipopolysaccharide activates transcription of SAA genes in rabbit fetuses [18] and that an activated-macrophage supernatant fraction is necessary for Hp gene transcription in Hep3B hepatoma cells [19].…”