Structure and Expression of Different Serum Amyloid A (SAA) Variants and their Concentration-Dependent Functions During Host Insults

Abstract

Serum amyloid A (SAA) is, like C-reactive protein (CRP), an acute phase protein and can be used as a diagnostic, prognostic or therapy follow-up marker for many diseases. Increases in serum levels of SAA are triggered by physical insults to the host, including infection, trauma, inflammatory reactions and cancer. The order of magnitude of increase in SAA levels varies considerably, from a 10- to 100- fold during limited inflammatory events to a 1000-fold increase during severe bacterial infections and acute exacerbations of chronic inflammatory diseases. This broad response range is reflected by SAA gene duplications resulting in a cluster encoding several SAA variants and by multiple biological functions of SAA. SAA variants are single-domain proteins with simple structures and few post-translational modifications. SAA1 and SAA2 are inducible by inflammatory cytokines, whereas SAA4 is constitutively produced. We review here the regulated expression of SAA in normal and transformed cells and compare its serum levels in various disease states. At low concentrations (10-100 ng/ml), early in an inflammatory response, SAA induces chemokines or matrix degrading enzymes via Toll-like receptors and functions as an activator and chemoattractant through a G protein-coupled receptor. When an infectious or inflammatory stimulus persists, the liver continues to produce more SAA (≥ 1000 ng/ml) to become an antimicrobial agent by functioning as a direct opsonin of bacteria or by interference with virus infection of host cells. Thus, SAA regulates innate and adaptive immunity and this information may help to design better drugs to treat specific diseases.

Fig. (1)

Nucleotide sequences of the coding regions from the human SAA genes. Nucleotide sequences of the coding regions from SAA1α [18], -ß [19] and -γ [19], SAA2α [18] and -ß [18], SAA3 [16] and SAA4 [7], arranged in codons, are shown. Identical nucleotides with SAA1α are not shown in the sequences of the other SAA1 and SAA2 genes. The sequence coding for the signal peptide (18 amino acids) is included. The stop codon (TGA) is marked in bold. Because of the single base insertion in the SAA3 gene, the stop signal already occurs in codon 43. Nucleotides in SAA3 and SAA4 differing from SAA1α are underlined. Compared to the SAA1α gene sequence, a single base insertion in codon 31 and an insertion of eight codons (codons 70-77) are present in the SAA3 and SAA4 genes, respectively. Exon boundaries are situated in between the shaded nucleotides. The exon boundaries within the SAA1ß and -γ and SAA2α and -ß genes are identical to those of the SAA1α gene.

Fig. (2)

Production of A-SAA and its chemotactic and cytokine inducing activities.