Regulation of serum amyloid A protein expression during the acute-phase response

Abstract

The acute-phase (AP) serum amyloid A proteins (A-SAA) are multifunctional apolipoproteins which are involved in cholesterol transport and metabolism, and in modulating numerous immunological responses during inflammation and the AP response to infection, trauma or stress. During the AP response the hepatic biosynthesis of A-SAA is up-regulated by pro-inflammatory cytokines, and circulating concentrations can increase by up to 1000-fold. Chronically elevated A-SAA concentrations are a prerequisite for the pathogenesis of secondary amyloidosis, a progressive and fatal disease characterized by the deposition in major organs of insoluble plaques composed principally of proteolytically cleaved A-SAA, and may also contribute to physiological processes that lead to atherosclerosis. There is therefore a requirement for both positive and negative control mechanisms that permit the rapid induction of A-SAA expression until it has fulfilled its host-protective function(s) and subsequently ensure that its expression can be rapidly returned to baseline. These mechanisms include modulation of promoter activity involving, for example, the inducer nuclear factor kappaB (NF-kappaB) and its inhibitor IkappaB, up-regulatory transcription factors of the nuclear factor for interleukin-6 (NF-IL6) family and transcriptional repressors such as yin and yang 1 (YY1). Post-transcriptional modulation involving changes in mRNA stability and translation efficiency permit further up- and down-regulatory control of A-SAA protein synthesis to be achieved. In the later stages of the AP response, A-SAA expression is effectively down-regulated via the increased production of cytokine antagonists such as the interleukin-1 receptor antagonist (IL-1Ra) and of soluble cytokine receptors, resulting in less signal transduction driven by pro-inflammatory cytokines.

Apolipoprotein A-V

“…Although the most up-regulated gene (amyloid A) might reflect an acute phase reaction (33), all the other eight known genes have been associated with liver regeneration or with cell proliferation in general: fibronectin (34), an intracisternal-A particle element (35), gamma-actin (36), and ribophorin I (37) with liver regeneration; ␣2-macroglobulin with hepatocyte proliferation in vitro (38); ribosomal protein S5 with protein synthesis (39); ribosomal protein L13 (which is similar to the human breast basic conserved 1 gene) with breast cancer (40); and the chaperonin-containing TCP-1 gamma subunit with protein folding (41). The associations of these genes with cell proliferation indicate that the applied subtraction technique was a valid method for identifying regeneration-related genes.…”

Pulmonary and Systemic Endotoxin Tolerance in Preterm Fetal Sheep Exposed to Chorioamnionitis

“…SAA3 is a class of acute-phase reactant proteins whose transcription is robustly induced by LPS exposure (27). Control animals had minimal expression of SAA3 mRNA in the lung and the liver (Fig.…”

Serum amyloid A and TNF? in serum and milk during experimental endotoxin mastitis

“…SAA has been shown to reflect the severity of mastitis; cows with clinical mastitis had almost 100-fold levels of SAA in serum and milk compared with healthy cows [5]. SAA is mainly produced in the liver but is also produced extrahepatically by macrophages, endothelial cells and smooth-muscle cells [5,12,17,30]. The effects of SAA may differ locally and systemically and may be concentrationdependent [30].…”